WO2025199182A1 - Traitement par acide 4-hydroxybenzoïque pour augmenter la production de coq10 - Google Patents

Traitement par acide 4-hydroxybenzoïque pour augmenter la production de coq10

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Publication number
WO2025199182A1
WO2025199182A1 PCT/US2025/020495 US2025020495W WO2025199182A1 WO 2025199182 A1 WO2025199182 A1 WO 2025199182A1 US 2025020495 W US2025020495 W US 2025020495W WO 2025199182 A1 WO2025199182 A1 WO 2025199182A1
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group
subject
hma
hpdl
disease
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WO2025199182A8 (fr
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Michael Pacold
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New York University NYU
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New York University NYU
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • CoQ10 is a lipophilic antioxidant critical for control of reactive oxygen species in biological membranes and for activity of the mitochondrial electron transport chain (FIG.10) (reviewed in(5)).
  • NEDSWMA is the latest addition to the family of primary CoQ10 deficiencies, a group of rare mitochondrial diseases caused by defects in CoQ10 biosynthesis. Patients with these conditions develop a variety of symptoms, with nearly all of them presenting with progressive encephalopathies. The overall success rate of treating patients with CoQ10 deficiencies with CoQ10 supplementation therapies is less than 30% (6). NEDSWMA is refractory to CoQ10 supplementation therapy.
  • Patients with mitochondrial diseases tend to present with incremental physical deterioration followed by rapid decompensation upon exposure to a stressor such as an infection.
  • HPDL 4-Hydroxyphenylpyruvate dioxygenase-like
  • 4- HMA is the first committed intermediate in the biosynthesis pathway for 4-hydroxybenzoate (4- HB), the immediate precursor of the Coenzyme Q10 (CoQ10) headgroup.
  • 4- HB 4-hydroxybenzoate
  • CoQ10 Coenzyme Q10
  • Hpdl -/- mice a model for NEDSWMA, develop spastic paresis and die by post-natal day 15 (P15).
  • No disease- modifying therapies for primary CoQ 10 deficiencies are currently available.
  • Hpdl -/- mouse pups have defects in cortical and cerebellar development consistent with mitochondrial disease. Labeled 4-HMA and 4-HB enter the brains of Hpdl -/- mice and are incorporated into CoQ 9 , the mouse equivalent of human CoQ 10 .
  • Oral treatment of Hpdl -/- pups with 4-HMA or 4-HB restores cerebellar architecture and Purkinje cell function, enables Hpdl -/- mice to live into adulthood, and substantially improves their motor function.
  • CoQ10, CoQ9, and soluble CoQ derivatives do not improve the overall survival of Hpdl -/- mice.
  • Our work suggests that 4-HMA and 4-HB treatment can modify the course of NEDSWMA and other diseases driven by loss of CoQ10 headgroup synthesis.
  • FIGS.1A-1H show that mammalian CoQ headgroup intermediates improve the survival of Hpdl -/- mice, and are incorporated into CoQ 9 in vivo.
  • FIG.1A shows the mammalian CoQ headgroup synthesis pathway. Tyrosine is deaminated to 4-hydroxyphenylpyruvate (4- 4 309005815v2 Attorney Docket No.: 243735.000414 HPPA). HPDL coverts 4-HPPA to 4-hydroxymandelate (4-HMA).4-HMA is converted to 4- hydroxybenzoate (4-HB), the immediate precursor of the CoQ headgroup.
  • FIG.1B is a graph showing that Hpdl -/- pups exhibit significant weight loss by post-natal day 10 (P10) relative to Hpdl +/+ and Hpdl +/- pups. Error bars represent median ⁇ interquartile range.
  • FIG.1C is a graph showing that Hpdl -/- pups die by P15. Hpdl +/+ and Hpdl +/- pups survive >1 year.
  • FIG.1D is a graph showing that all Hpdl -/- pups have observed seizures. No Hpdl +/+ or Hpdl +/- pups had observed seizures.
  • FIG.1E is a graph showing that Hpdl -/- pups have lower plasma 4-HMA than Hpdl +/+ or Hpdl +/- pups at P10. Error bars represent mean ⁇ standard deviation.
  • FIG.1F is a graph showing that oral supplementation with 4-HMA and 4-HB (10 mg/kg, once daily) improves the overall survival of Hpdl -/- pups. Oral supplementation of CoQ 9 , CoQ 10 and related compounds does not improve Hpdl -/- pup survival.
  • FIG.1G is a schematic showing the incorporation of 13 C from 13 C6-4-HMA and 13 C6-4-HB into mouse CoQ9.
  • FIGS.2A-2E show that 4-HMA supplementation restores the histologic appearances of the brains of Hpdl -/- mice.
  • FIG.2A shows representative electron micrographs of cortex (panels A-D) and cerebellum (panels E-H) in P11 Hpdl +/+ , Hpdl +/- , and Hpdl -/- mouse pups reveal minimal changes in cortical ultrastructure.
  • the mitochondria (marked by arrowheads) in Hpdl +/+ (panels A, E) and Hpdl +/- (panels B, F) mouse pups are intact, but the mitochondria in the cerebella of Hpdl -/- mouse pups (panel G) are fragmented.
  • FIG.2B shows quantitation of mitochondrial perimeter in electron micrographs of the cerebellum in P11 Hpdl +/+ , Hpdl +/- , and Hpdl -/- mouse pups, and Hpdl -/- mouse pups treated with 4-HMA.
  • Mitochondria in the Hpdl -/- mouse pups are smaller than in the Hpdl +/+ and Hpdl +/- pups.4-HMA treatment improves the size of the mitochondria in the Hpdl -/- pups, but not to the size of mitochondria in Hpdl +/+ pups.
  • FIG.2C shows that P11 Hpdl -/- pups exhibit marked cerebellar atrophy (panel C), with Purkinje cells (arrowheads) showing vacuolization and intracellular 5 309005815v2 Attorney Docket No.: 243735.000414 edema, thinning of the inner granular layer (IGL) and molecular layer, and compaction of the external granular layer (EGL) (panels G, K). These abnormalities are improved to near-wild-type pups by supplementation with 4-HMA (panels D, H, L).
  • FIG.2D shows quantitation of B. Hpdl -/- mouse pups have a thinner IGL than Hpdl +/+ or Hpdl +/- pups.
  • FIG.2E shows that P11 Hpdl -/- pups exhibit loss of normal cortical layers of the cerebral cortex (panels C, G, K), as well as edema, shrinking of the cortical neurons, and red neurons (marked by arrowheads).
  • FIGS 3A-3F show that 4-HMA supplementation improves the behavioral phenotypes of Hpdl -/- mice and electrophysiologic behavior of Purkinje cells from Hpdl -/- pups.
  • FIG.3A shows that patch-clamping of Purkinje cells in brain slices from P8-10 pups demonstrates increased input resistance and membrane capacitance in Purkinje cells from Hpdl -/- pups in comparison to Purkinje cells from Hpdl +/+ and Hpdl +/- pups.
  • Treatment of Hpdl -/- pups with 4-HMA decreases Purkinje cell input resistance and increases membrane capacitance to levels comparable to more mature Purkinje cells (FIG.6E).
  • FIG.3E shows that Hpdl -/- mice treated with 4-HMA have similar performance to Hpdl +/+ and Hpdl +/- mice in the transverse beam test, a measure of balance.
  • FIG.3F shows relative to Hpdl +/+ mice, forelimb grip strength is reduced in Hpdl +/- mice as well as Hpdl -/- mice treated with 4-HMA.
  • Hindlimb grip strength is identical in Hpdl +/+ , Hpdl +/- , and Hpdl -/- mice treated with 4-HMA from P3 until 4-6 weeks. Data presented are mean ⁇ standard deviation, as well as raw data.
  • FIG.4A shows lactate/pyruvate ratio in plasma from Hpdl +/+ , Hpdl +/- , and Hpdl -/- pups. Hpdl -/- pups have a higher lactate/pyruvate ratio than Hpdl +/+ and Hpdl +/- pups.
  • FIG.4B shows mouse dose-response of 4-HMA treatment in improving the survival of Hpdl -/- pups.4-HMA 6 309005815v2 Attorney Docket No.: 243735.000414 dosing of 10 mg/kg improves the 30-day survival of 90% of pups. Doses of 0.1 mg/kg or 1 mg/kg did not improve the overall survival of these.
  • FIG.4C shows MTD of 4-HMA and 4-HB, and half-life of 4-HMA and half-life of 4-HB dosed at treatment dose (10 mg/kg po), 500 mg/kg po, and 1 mg/kg IV. Data represent mean ⁇ standard deviation.
  • FIG.4D shows pharmacokinetic data for 4-HMA and 4-HB at 500 mg/kg po and 1 mg/kg IV.
  • FIG.4E shows treatment of Hpdl -/- pups with 4-HMA, the product of HPDL, and 4-HB, the immediate precursor of the CoQ headgroup, results in weight gain similar to Hpdl +/- pups. Error bars represent median ⁇ interquartile range.
  • FIG.4F shows Hpdl -/- pups are able to stand 3 days after supplementation with 4-HMA (10 mg/kg, oral administration).
  • FIG.4G shows effects of 4-HMA treatment on an Hpdl -/- pup. Two Hpdl -/- pups are on the right and two Hpdl +/- littermates are on the right.
  • FIG.4H shows CoQ 9 abundance and labeling from mouse brains following treatment with 13 C6-4-HMA starting at postnatal day 3.
  • 13 C6-4-HMA is incorporated into CoQ9 in Hpdl -/- mice, and increases brain CoQ9 relative to untreated mice.
  • 13 C6- 4-HMA is not incorporated into CoQ 9 in Hpdl +/+ mice and is incorporated into CoQ 9 at a lower fraction in Hpdl +/- mice. Significance was tested by two-way analysis of variance (ANOVA) followed by Tukey’s post-hoc test.
  • FIG.5A shows that P11 Hpdl -/- pups do not exhibit major changes in hippocampal histology in comparison to Hpdl +/+ pups, Hpdl +/- pups, and Hpdl -/- pups treated with 4-HMA.
  • FIGS.6A-6L show functional characteristics of Purkinje cells and additional behavioral and neurological tests of Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- mice.
  • FIG.6A shows that the I/V curves of Purkinje cells from P8-10 Hpdl -/- pups and 4-HMA-treated Hpdl -/- pups are significantly different from each other and from the I/V curves of Hpdl +/+ and Hpdl +/- pups, which are similar. P-values indicating statistical significance are listed.
  • the Hpdl -/- pups have a flatter I/V curve at hyperpolarized membrane potentials relative to the other curves due to a tighter grouping of currents at hyperpolarized membrane potentials (-100 to -60 mV) than the Hpdl +/+ and Hpdl +/- pups (see insert).
  • FIG.6B shows F/I curves of Purkinje cells from P8-10 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups. There were no significant differences in the linear portions of each curve between each group.
  • the insert shows the simple firing 7 309005815v2 Attorney Docket No.: 243735.000414 pattern of an immature Purkinje cell.
  • FIG.6C shows peak frequency of Purkinje cells from P8- 10 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups.
  • the 4-HMA treated Hpdl -/- group has higher peak frequency than any of the other groups. Differences in frequency were identified by two-way ANOVA followed by Dunnett’s multiple comparison test.
  • FIG.6D shows action potential characteristics of P8-10 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups. An average action potential is shown in panel A and the phase plane diagram is shown in panel B.
  • FIG.6E shows that HPDL supplementation restores input resistance and membrane capacitance of Purkinje cells from Hpdl -/- pups to levels comparable to Hpdl +/+ and Hpdl +/- pups at P17-19.
  • FIG.6F shows that the I/V curves of Purkinje cells from P17-19 Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- pups are similar.
  • FIG.6G shows F/I curves of Purkinje cells from P17-19 Hpdl +/+ , Hpdl +/- , Hpdl -/- and 4-HMA-treated Hpdl -/- pups. There were no significant differences in the linear portions of each curve between each group.
  • the insert shows the simple firing pattern of a more mature Purkinje cell.
  • FIG.6H shows peak frequency of Purkinje cells from P17-19 Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- pups. The peak frequencies in all three groups are comparable.
  • FIG.6I shows action potential characteristics of P17-19 Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- pups. An average action potential is shown in panel A and the phase plane diagram is shown in panel B.
  • the spike threshold, spike amplitude, and spike half-width 8 309005815v2 Attorney Docket No.: 243735.000414 are comparable in all three groups.
  • FIG.6J shows that forelimb grip strength is decreased in 4-6-week-old Hpdl +/- (p ⁇ 0.0001) and 4-HMA-treated Hpdl -/- mice (p ⁇ 0.0001) relative to Hpdl +/+ mice. Grip strength of all limbs is similar in Hpdl +/+ , Hpdl +/- , and 4-HMA- treated Hpdl -/- mice.
  • FIG.6L shows metabolic phenotypes such as food and water intake, activity, O 2 consumption, CO 2 production, and energy expenditure are similar in 4-6-week-old Hpdl +/+ , Hpdl +/- , and 4-HMA-treated Hpdl -/- mice, as measured in metabolic cages. Differences were identified by two-way ANOVA followed by Dunnett’s multiple comparison test.
  • FIG.7 shows safety data sheet for 4-hydroxybenzoic acid.
  • FIG.8 shows product specification for 4-hydroxybenzoic acid.
  • FIG.9 shows certificate of analysis for 4-hydroxybenzoic acid.
  • FIG.10 shows the mammalian CoQ10 headgroup synthesis pathway. HPDL converts 4-hydroxyphenylpyruvate to 4-hydroxymandalate (4-HMA ⁇ .4-HMA is converted to 4- hydroxybenzoic acid (4-HB), the immediate precursor of the CoQ10 headgroup. The COQ2 prenyltransferase conjugates 4-HB to polyprenyl pyrophosphate to form the skeleton of CoQ10, followed by headgroup modification to form the active molecule (reviewed in (5)).
  • FIG.11A shows triplicate injections demonstrating the reproducibility of co-elution of 100 ⁇ M unlabeled 4-hydroxybenzoic acid (unlabeled) and 13C6-4-hydroxybenzoic acid internal standard (labeled). These standards and the frozen 4-HB were run simultaneously.
  • FIG.11B shows stability of frozen 4-HB stocks (frozen at -20 ⁇ C for 3 months). The peak height at 200 ⁇ M is 7.6E7, which is about four times the peak height of 50 ⁇ M fresh 4-HB (1.45E7; panel A).
  • FIG.12 shows that parabens are mainly metabolized through hydrolysis supported by esterases and through glucuronidation catalyzed by UDP-glucuronosyltransferases (UGT) using UDP-glucuronic acid (UDPGA). They can also produce sulfoconjugates by sulfotransferase (ST) using 3’-phosphoadenosine 5’-phosphosulfate (PAPS) as the sulfate donor substrate, or 4- hydroxyhippuric acid by amino acid transferase (AT) using glycine as the donor substrate.
  • FIG.13 is a survival plot for treatment of Hpdl-/- mice with a 4-HB suspension stored at room temperature.
  • FIG.14 shows regrowth of hair in shaved 90-week-old-mice following treatment with systemic 4-HMA at 100 mg/kg two weeks prior to treatment. After week 5, topical 4-HMA at 100 mg/kg was applied every other day.
  • FIG.15 shows regrowth of hair in shaved 90-week-old-mice following topical treatment with 4-HMA (100 mg/mL) every other day.
  • the terms “about” or “approximately” for any numerical values or ranges indicate a suitable dimensional tolerance that allows the part or collection of components to function for its intended purpose as described herein. More specifically, “about” or “approximately” may refer to the range of values ⁇ 20% of the recited value, e.g. “about 90%” may refer to the range of values from 71% to 99%.
  • alkyl refers to an alkylene group.
  • certain compounds of the disclosure can be indicated to comprise “optionally substituted” moieties.
  • substituted whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent.
  • an “optionally substituted” group can have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure can be substituted with more than one substituent selected from a specified group, the substituent can be either the same or different at every position.
  • substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds.
  • stable refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.
  • a substituent e.g., -B
  • the “pharmaceutically acceptable salts” include a subset of the “salts” described above which are conventional non-toxic salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p.1418 and Berge, SM et al, Journal of Pharmaceutical Science, 1977, 66, 1, 1-19.
  • pharmaceutically acceptable salts can comprise a suitable cation selected from aluminum, arginine, benzathine, calcium, chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, lysine, magnesium, histidine, lithium, meglumine, potassium, procaine, sodium, triethylamince, or zinc.
  • pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • prodrug as used herein includes a chemical which may be transformed in vivo to a pharmacologically active drug.
  • metabolite as used herein includes a chemical that a given agent is transformed into in vivo.
  • the enantiomeric excess, or “ee,” for a given pair of enantiomers is the percentage of the major enantiomer less the percentage of the minor enantiomer.
  • a “racemate” or “racemic mixture” is an equal mixture of two enantiomers and therefore has 0% ee.
  • enantiomerically enriched or “enantioenriched” as used herein includes compounds that are mixtures with one enantiomer's being present in excess over the other (ee >0% and ⁇ 100%). For example, a sample of 40% ee consists of 70% of the major enantiomer and 30% of the minor enantiomer.
  • enantiomerically pure or “enantiopure” as used herein includes compounds where the quantification of the minor enantiomer becomes difficult, e.g., with an ee of 99% or greater. Ideally, enantiopure compounds consist of a single enantiomer only.
  • sample includes any biological specimen obtained from a subject or patient.
  • Samples that can be used in the methods of the present disclosure include, without limitation, tumor sample, whole blood, plasma, serum, red blood cells, white blood cells (e.g., peripheral blood mononuclear cells (PBMC), polymorphonuclear (PMN) cells), ductal lavage fluid, nipple aspirate, lymph (e.g., disseminated tumor cells of the lymph node), bone marrow aspirate, saliva, urine, stool (i.e., feces), sputum, bronchial lavage fluid, tears, fine needle aspirate (e.g., harvested by random periareolar fine needle aspiration), any other bodily fluid, a tissue sample such as a biopsy (e.g., needle biopsy), and cellular extracts thereof.
  • PBMC peripheral blood mononuclear cells
  • PMN polymorphonuclear
  • the sample when the subject is a pregnant female, the sample may be a fetal DNA sample (e.g., cell-free fetal DNA (cffDNA)).
  • a fetal DNA sample e.g., cell-free fetal DNA (cffDNA)
  • the term “subject” or “patient” refers to mammals and includes, without limitation, human and veterinary animals. In a preferred embodiment, the subject is human.
  • the subject is a pediatric subject 0 to 18 years of age. In some embodiments, the subject is a child, including an unborn fetus, a newborn, an infant, or a toddler.
  • treating an unborn fetus using methods described herein may involve treating a pregnant female carrying the unborn fetus.
  • the subject is a pediatric subject 0 to 18 month of age, 0 to 2 years of age, 0 to 10 years of age, 0 to 18 years of age, or 0 to 21 years of age.
  • the subject is an adult. In some embodiments, the subject is an elderly adult. In some embodiments, the subject is 65 year old adult or older.
  • the subject is a male. In some embodiments, the subject is a male 30 years or older, 35 years or older, 40 years or older, 45 years or older, 50 years or older, 55 years or older, 60 years or older, or 65 years or older.
  • the terms “treat” or “treatment” of a state, disorder or condition include: (1) preventing or delaying the appearance of at least one clinical or sub-clinical symptom of the state, disorder or condition developing in a subject that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition; or (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or sub-clinical symptom thereof; or (3) relieving the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or sub- 13 309005815v2 Attorney Docket No.: 243735.000414 clinical symptoms.
  • an “effective amount” of a compound described herein refers to an amount sufficient to elicit the desired biological response, i.e., treating the state, disorder or condition.
  • the effective amount of a compound described herein may vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the condition being treated, the mode of administration, and the age and health of the subject.
  • An effective amount encompasses therapeutic and prophylactic treatment.
  • reference to a component is intended also to include composition of a plurality of components.
  • References to a composition containing “a” constituent is intended to include other constituents in addition to the one named.
  • the terms “a,” “an,” and “the” do not denote a limitation of quantity, but rather denote the presence of “at least one” of the referenced item.
  • terminology will be resorted to for the sake of clarity. It is intended that each term contemplates its broadest meaning as understood by those skilled in the art and includes all technical equivalents which operate in a similar manner to accomplish a similar purpose.
  • Such other materials not described herein can include, but are not limited to, materials that are developed after the time of the development of the invention, for example. Any dimensions listed in the various drawings are for illustrative purposes only and are not intended to be limiting. Other dimensions and proportions are contemplated and intended to be included within the scope of the invention.
  • Compounds of the Disclosure [0055] In one aspect, provided herein is a compound having the structure of Formula (I): R 3 O , wherein: R 1 is selected from the group ; R2 is selected from the group R3 is selected from the group consisting of H and C1-C3 alkyl, and R4 is selected from the group consisting of H , or pharmaceutically acceptable salt thereof. [0056] In one embodiment, R1 is H.
  • R 2 is H.
  • R 3 is H. 15 309005815v2 Attorney Docket No.: 243735.000414
  • R3 is methyl.
  • R4 is H.
  • R4 is H.
  • R4 is H.
  • R4 is H.
  • R4 is selected from one of Formula (I): or a pharmaceutically R1 is selected from the group R4 is selected from the group consisting of H .
  • the compound of the structure according to Formula (III): or a pharmaceutically R1 is selected from the group R4 is selected from the group consisting of H .
  • the compound having of Formula (I) is selected from the group consisting of: 16 309005815v2 Attorney Docket No.: 243735.000414 , [0067] In one embodiment, the compound having the structure of Formula (I) is selected from the group consisting of: a [0068] In one aspect, the present invention provides 2-hydroxy-2-(4-hydroxyphenyl)acetic acid (also known as 4-hydroxymandelic acid (4-HMA)), or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystal, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof. .
  • 2-hydroxy-2-(4-hydroxyphenyl)acetic acid also known as 4-hydroxymandelic acid (4-HMA)
  • 4-HMA 4-hydroxymandelic acid
  • R- and the S- enantiomers of 4-HMA depicted below: 17 309005815v2 Attorney Docket No.: 243735.000414 .
  • the (R)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.
  • 4-HMA is provided as the enantiopure R-enantiomer (R)-4- HMA.
  • 4-HMA is provided as an enantioenriched mixture of the S- enantiomer, i.e., (S)-4-HMA.
  • the (S)-4-HMA is present with an enantiomeric excess (ee) of about 20% or greater, or about 30% or greater, or about 40% or greater, or about 50% or greater, or about 60% or greater, or about 70% or greater, or about 80% or greater, or about 85% or greater, or about 90% or greater, or about 95% or greater, or about 96% or greater, or about 97% or greater, or about 98% or greater, or about 99% or greater, or about 99.5% or greater, or about 99.9% or greater.
  • ee enantiomeric excess
  • the (S)-4-HMA is present with an enantiomeric excess (ee) of at least about 20%, or at least about 30%, or at least about 40%, or at least about 50%, or at least about 60%, or at least about 70%, or at least about 80%, or at least about 85%, or at least about 90%, or at least about 95%, or at least about 98%, or at least about 99%.
  • 4-HMA is provided as the enantiopure S-enantiomer (S)-4- HMA.
  • compositions and Administration [0077]
  • the present invention also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, wherein R1, R2, R3, and R4 are as defined above.
  • the present invention also provides pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt, solvate, hydrate, polymorph, co-crystals, tautomer, stereoisomer, isotopically labeled derivative, or prodrug thereof, and optionally a pharmaceutically acceptable excipient.
  • Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology.
  • the amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage. 19 309005815v2 Attorney Docket No.: 243735.000414 [0081] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. The composition may comprise between 0.1% and 100% (w/w) active ingredient.
  • compositions used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.
  • Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.
  • Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof.
  • EDTA ethylenediaminetetraacetic acid
  • salts and hydrates thereof e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like
  • citric acid and salts and hydrates thereof e.g., citric acid mono
  • Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, 22 309005815v2 Attorney Docket No.: 243735.000414 magnesium hydroxide, aluminum hydroxide, al
  • Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
  • Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea
  • Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.
  • Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
  • the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • the conjugates of the invention are mixed with solubilizing agents such as CremophorTM, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof. 23 309005815v2 Attorney Docket No.: 243735.000414 [0098]
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the conjugates of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol, or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or (a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as glycerol, (d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, 24 309005815v2 Attorney Docket No.: 243735.000414 and sodium carbonate, (e) solution retarding agents such as paraffin, (f) absorption accelerators such as quaternary ammonium compounds, (g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate,
  • encapsulating compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active ingredient can be in a micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings, and other coatings well known in the pharmaceutical formulating art.
  • the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch.
  • inert diluent such as sucrose, lactose, or starch.
  • Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of encapsulating compositions which can be used include polymeric substances and waxes.
  • Dosage forms for topical and/or transdermal administration of a compound of this invention may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, 25 309005815v2 Attorney Docket No.: 243735.000414 inhalants and/or patches.
  • the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier or excipient and/or any needed preservatives and/or buffers as can be required.
  • the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body.
  • Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium.
  • the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel.
  • Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices. Intradermal compositions can be administered by devices which limit the effective penetration length of a needle into the skin. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration. Jet injection devices which deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle which pierces the stratum corneum and produces a jet which reaches the dermis are suitable.
  • Formulations suitable for topical administration include, but are not limited to, liquid and/or semi-liquid preparations such as liniments, lotions, oil-in-water and/or water-in-oil emulsions such as creams, ointments, and/or pastes, and/or solutions and/or suspensions.
  • Topically administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent.
  • Formulations for topical administration may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity.
  • a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers, or from about 1 to about 6 nanometers.
  • compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self-propelling solvent/powder dispensing container such as a device 26 309005815v2 Attorney Docket No.: 243735.000414 comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container.
  • Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers.
  • Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.
  • Low boiling propellants generally include liquid propellants having a boiling point of below 65° F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition.
  • the propellant may further comprise additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).
  • Pharmaceutical compositions of the invention formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device.
  • Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate.
  • a flavoring agent such as saccharin sodium
  • a volatile oil such as a liquid oil
  • a buffering agent such as a liquid oil
  • a surface active agent such as methylhydroxybenzoate
  • a preservative such as methylhydroxybenzoate.
  • the droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.
  • Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention.
  • Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered by rapid inhalation through the nasal passage from a container of the powder
  • Formulations for nasal administration may, for example, comprise from about as little as 0.1% (w/w) to as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the 27 309005815v2 Attorney Docket No.: 243735.000414 invention can be prepared, packaged, and/or sold in a formulation for buccal administration.
  • Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein.
  • formulations for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient.
  • Such powdered, aerosolized, and/or aerosolized formulations when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.
  • a pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation for ophthalmic administration.
  • Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier or excipient.
  • Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein.
  • Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.
  • the desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks.
  • the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).
  • the effective amount of the compound in the composition that may be used in accordance with the present disclosure may vary from about 0.0001 mg/kg to about 1000 mg/kg in one or more dose administrations for one or several days (depending on the mode of administration).
  • the compounds and compositions provided herein can be administered to a subject once a week, twice a week, three times a week, or four or more times a week.
  • the compounds and compositions provided herein can also be administered to a subject once every two weeks, once every three weeks, once a month, once every two month, once every three month, once every four month, once every five month, once every six month, once every seven month, once every eight month, once every nine month, once every ten month, once every eleven month, once a year, or once every two years.
  • the heart disease that can be treated include, but are not limited to, heart failure, high blood pressure, recovery post cardiac surgery, and statin-induced myopathy.
  • the neurodegenerative disease that can be treated include, but are not limited to, Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis (ALS), and demyelinating and white matter disease.
  • the neurodevelopmental disease is cerebral palsy.
  • the pulmonary disease is chronic obstructive pulmonary disease (COPD) or asthma.
  • COPD chronic obstructive pulmonary disease
  • the muscle disease is muscular dystrophy.
  • the liver disease is characterized by toxicity due to statins or liver injury.
  • the pancreatic disease is selected from the group consisting of type 1 diabetes, type 2 diabetes, and exocrine insufficiency. 33 309005815v2 Attorney Docket No.: 243735.000414
  • the oral disease is selected from the group consisting of tooth decay, periodontitis, and gum decay.
  • the ophthalmic disease is selected from the group consisting of macular degeneration, cataract formation, retinal detachment, and retinitis pigmentosa.
  • the hearing disease is hearing loss.
  • the disease of pregnancy is placental insufficiency or pre- eclampsia.
  • the disease of prematurity is selected from the group consisting of prematurity, retinopathy of prematurity, and cerebral palsy.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in improving wound healing in a subject.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a neurodevelopmental disorder with spastic paresis and brain white matter abnormalities.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a subject having a white matter abnormality.
  • the subject has 4-hydroxyphenylpyruvate dioxygenase-like (HPDL) deficiency.
  • HPDL 4-hydroxyphenylpyruvate dioxygenase-like
  • the subject has a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway.
  • the mutation is homozygous.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a subject having a variant in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in improving physical performance and energy production in a subject.
  • the treatment results in one or more of decreasing fatigue, increasing strength and stamina, increasing functional performance, and improving balance.
  • 34 309005815v2 Attorney Docket No.: 243735.000414
  • the compound(s) or pharmaceutical compositions of the present disclosure when used in combination with an antacid may be useful in treating a 4- hydroxyphenylpyruvate dioxygenase-like (HPDL)-related disease or disorder in a subject.
  • HPDL 4- hydroxyphenylpyruvate dioxygenase-like
  • Suitable antacid that can be used include, but are not limited to, aluminum, calcium, magnesium, and sodium salts.
  • the antacid is selected from the group consisting of aluminum hydroxide, magnesium hydroxide, sucrose/calcium carbonate, sodium citrate, citric acid, sodium bicarbonate, tartaric acid, and alginic acid.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in treating a neurodegenerative or psychiatric disease.
  • the child when the subject being treated is a child, the child may be treated with the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), in utero, immediately after birth, or in postpartum days.
  • the method may involve treating a newborn or infant by administering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 4-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the newborn or infant.
  • the method may involve treating an unborn fetus by administering the compound(s) or pharmaceutical compositions comprising the compound(s) described herein, such as 44-HMA (e.g., (R)-4-HMA), 4-HB, or a compound of Formula (I), to the pregnant female.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful in accelerating, promoting, or restoring hair growth in a subject.
  • the disclosed methods may be used to promote hair growth on any body surface of a subject where hair growth is desired, including, for example, the scalp, chest, and face (e.g., beard, eyebrows, scars, etc.).
  • hair growth over the entire body surface may be desired.
  • Particular methods involve growing hair on all or part of the scalp (such as, an area of premature balding or hair thinning) or in an area of alopecia-affected skin of a subject.
  • “Promoting hair growth” as used herein is intended to have its broadest possible meaning.
  • promoting hair growth is to decrease a rate of hair loss in an 35 309005815v2 Attorney Docket No.: 243735.000414 area that normally has hair such that (i) on-going hair loss occurs at a slower rate (e.g., retarded or slowed hair loss); (ii) hair loss is substantially stopped (e.g., the rate of hair loss is substantially the same as the rate of hair growth); or (iii) hair loss is reversed (e.g., the rate of hair loss is lower than the rate of hair growth) such that the area of interest exhibits a net increase in the amount of hair.
  • a slower rate e.g., retarded or slowed hair loss
  • hair loss is substantially stopped (e.g., the rate of hair loss is substantially the same as the rate of hair growth)
  • hair loss is reversed (e.g., the rate of hair loss is lower than the rate of hair growth) such that the area of interest exhibits a net increase in the amount of hair.
  • promoting hair growth is to induce hair growth on a substantially hairless surface capable of growing hair, such as a body surface that formerly had, but has lost substantially all, hair.
  • promoting hair growth includes inducing or stimulating hair growth on a hair-containing surface that is not experiencing hair loss; for example, increasing the rate at which hair-growing cells grow hair and/or increasing the number of hair-growing cells (e.g., increasing the number of hair follicles or the number of follicles in the anagen phase). Such latter method embodiments may be useful to increase hair density or length.
  • Promotion of hair growth also includes decreased shedding (either at the roots or by breaking/fragility) measured, for example, by hair pull tests.
  • the promotion of hair growth can be measured using any method known in the art or any of the methods disclosed herein, for example, quantitative and qualitative comparison of treated areas or subjects to controls.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating hair loss in a subject.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating a condition or disorder affecting hair growth in a subject, such as baldness, alopecia, or scarring.
  • the compound(s) or pharmaceutical compositions of the present disclosure maybe administered in combination with one or more additional therapeutic agents.
  • the treatment further comprises detecting in a biological sample obtained from the subject the presence of the one or more variants in the HPDL gene, any other gene in the CoQ headgroup synthesis pathway, or any gene controlling the CoQ headgroup synthesis pathway prior to said administration.
  • the treatment further comprises detecting plasma 4-HMA concentration in a biological sample obtained from the subject prior to said administration.
  • Suitable biological sample can comprise peripheral blood mononuclear cells or a biopsy specimen. 36 309005815v2 Attorney Docket No.: 243735.000414
  • the subject is a pregnant female and the biological sample is a fetal DNA sample.
  • the fetal DNA sample can be obtained, for example, by circulating fetal DNA isolation, chorionic villus sampling, or amnioscentesis.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for treating a 4-hydroxyphenylpyruvate dioxygenase-like (HPDL)- related disease or disorder in a subject.
  • the method includes detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and administering to the subject having a reduced plasma 4-HMA concentration ( ⁇ 20 nM) a therapeutically effective amount of the compound(s) or pharmaceutical compositions of the present disclosure.
  • the compound(s) or pharmaceutical compositions of the present disclosure may be useful for increasing CoQ10 biosynthesis in a subject.
  • the method includes detecting in a biological sample obtained from the subject the plasma 4-HMA concentration; and administering to the subject having a reduced plasma 4-HMA concentration a therapeutically effective amount of the compound(s) or pharmaceutical compositions of the present disclosure.
  • EXAMPLES [00171] The following examples are provided to further describe some of the embodiments disclosed herein. The examples are intended to illustrate, not to limit, the disclosed embodiments. [00172] Hpdl -/- mice recapitulate the symptoms of patients with NEDSWMA.
  • Hpdl -/- pups initially are identical in appearance to wild-type animals, but by post-natal day 5 (P5) Hpdl -/- pups develop movements consistent with spastic paresis and epileptic seizures, and stop gaining weight 19 . By P15, all Hpdl -/- pups are dead. In contrast, Hpdl +/- pups uniformly reach adulthood. [00173] Disease-modifying treatments for mitochondrial diseases, including NEDSWMA and other primary CoQ 10 deficiencies, remain an unmet medical need.
  • CoQ 10 supplementation can improve myositis, lactic acidosis, and other peripheral symptoms of primary CoQ10 deficiencies
  • CoQ10 supplementation controls the neurological symptoms of primary CoQ10 deficiency or other mitochondrial diseases less than 30% of the time 28 . It is not clear if correction of the underlying biochemical defects in primary CoQ10 deficiencies can modify the course of these diseases effectively or robustly. Specifically, the capacity of 4-HMA and 4-HB to restore CoQ synthesis and relieve the symptoms of HPDL loss in intact organisms is unknown. [00174] It was assumed that treatment of Hpdl -/- mice with 4-HMA would bypass loss of the CoQ10 headgroup biosynthesis and enable CoQ10 synthesis in situ.
  • the present disclosure shows 37 309005815v2 Attorney Docket No.: 243735.000414 that Hpdl -/- mice with 4-HMA, the product of HPDL, and 4-HB, the immediate precursor of the CoQ headgroup, near-uniformly live to adulthood and have motor phenotypes indistinguishable from Hpdl +/- littermates. 13 C-labeled 4-HMA and 4-HB were incorporated into CoQ 9 in the brains of treated mice. These experiments demonstrate that 4-HMA and 4-HB are physiologically important for CoQ10 synthesis during development and suggest that 4-HMA or 4-HB treatment may treat patients with NEDSWMA and SPG83 associated with HPDL variants.
  • Hpdl -/- pups develop symptoms of neurodevelopmental disease and have low plasma 4- HMA concentrations.
  • 4-HMA is an intermediate in a non-canonical tyrosine catabolism pathway required for the synthesis of the CoQ 10 headgroup in mammals (FIG.1A). It was hypothesized that deletion of Hpdl would result in decreased plasma concentrations of 4-HMA in Hpdl -/- pups relative to Hpdl +/- or Hpdl +/+ pups.
  • Hpdl +/- mice C57BL/6NCrl- Hpdlem1(IMPC)Mbp /Mmucd
  • KOMP/MMRRC Knockout Mouse Project / Mutant Mouse Resource & Research Center
  • Hpdl -/- pups initially have the same weight as wild-type pups, but do not gain weight following birth (FIG. 1B)
  • Hpdl -/- pups develop seizures, lose weight, and die by P15 (FIGS. 1C-1D).
  • Hpdl -/- pups have lower plasma [4-HMA] than Hpdl +/+ or Hpdl +/- pups (FIG.1E) and a higher plasma lactate/pyruvate ratio (Fig.4A).
  • Oral treatment with 4-HMA or 4-HB improves the lifespan of Hpdl -/- pups
  • 4-HMA the product of HPDL, or 4-HB, the immediate precursor of the CoQ 10 headgroup
  • Hpdl -/- pups treated with 4-HMA or 4-HB uniformly lived to ages of 12 months or more (FIG. 1F).
  • oral treatment of Hpdl -/- pups with CoQ 9 , CoQ 10 , the CoQ analog Idebenone, and mitochondrially targeted antioxidant MitoTEMPO 30-32 did not improve their survival (FIG.1F).
  • 4-HMA and 4-HB are incorporated into mouse brain CoQ9 38 309005815v2 Attorney Docket No.: 243735.000414 [00180]
  • Hpdl +/+ , Hpdl +/- , and Hpdl -/- pups with 13 C 6 -4-HB and 13 C 6 -4-HMA at 10 mg/kg from P3 to P20 and measured the incorporation of 13 C into CoQ9 in the brain by liquid chromatography-mass spectrometry (FIG.1G).
  • Hpdl +/+ and Hpdl +/- mice were derived from 4-HMA or 4-HB, but Hpdl -/- pups derived 50% of CoQ 9 from exogenously administered 13 C 6 -4-HB and 13 C 6 -4-HMA (FIG. 1H).
  • No CoQ 9 was labeled in P12 Hpdl -/- pups that were not fed 13 C 6 -4-HB or 13 C 6 -4-HMA.
  • Hpdl -/- pups not fed 13 C6-4-HMA exhibited reduced CoQ9 relative to Hpdl -/- pups fed 13 C6-4-HMA (FIG.4H).
  • Hpdl -/- pups There also was loss of normal architecture of the cerebellar Purkinje cell layer (EGL) (FIG.2C). Hpdl -/- pups also had decreased inner granular layer (IGL) thickness (FIG.2D). These findings are consistent with decreased proliferation of cerebellar granule cells and a failure of granule cells to successfully establish the IGL. Cortical neurons in Hpdl -/- pups also show vacuolation, decreased nuclear area, and loss of normal cortical architecture with neuronal microcolumns, edema and neuronal shrinking in the cortex relative to Hpdl +/- pups (FIG. 2E).
  • the P8-10 group contained Hpdl +/+ , Hpdl +/- , Hpdl- /- pups, and Hpdl -/- pups treated with 4-HMA.
  • the P17-19 group did not have untreated Hpdl -/- pups as these animals die by P15.
  • there was a significant increase in input resistance (Ri) and significant reduction in membrane capacitance (Cm) in cerebellar Purkinje cells in Hpdl -/- mice in comparison to Hpdl +/+ and Hpdl +/- mice (FIGS. 3A-3B, Table 1).
  • Cerebellar Purkinje cells from Hpdl -/- pups had a tighter grouping of currents at hyperpolarized membrane potentials (-100 to -60 mV) relative to the Hpdl +/+ group 40 309005815v2 Attorney Docket No.: 243735.000414 (FIGS.6A-6B, insets). This grouping resulted in a flatter I/V curve at hyperpolarized membrane potentials that was significantly different from the I/V curves of cerebellar Purkinje cells from Hpdl +/+ and Hpdl +/- pups (FIG. 6A).
  • the I/V curve of cerebellar Purkinje cells in Hpdl -/- pups treated with 4-HMA was steeper than the curves of the Hpdl +/+ , Hpdl +/- , and Hpdl -/- pups, and closer in slope and magnitude to the I/V curves of P17-19 cerebellar Purkinje cells.
  • the I/V curve of cerebellar Purkinje cells from 4-HMA-treated Hpdl -/- pups was indistinguishable from curves from Hpdl +/+ and Hpdl +/- pups (FIGS.6F-6G).
  • Cerebellar Purkinje cells from Hpdl -/- pups treated with 4-HMA had a higher firing rate than Hpdl +/+ and Hpdl +/- cerebellar Purkinje cells. These differences were consistent with immaturity of Hpdl -/- cerebellar Purkinje cells relative to Hpdl +/+ and Hpdl +/- pups, and with accelerated maturation of 4-HMA-treated Hpdl -/- cerebellar Purkinje cells. These differences disappeared by P17-19 (FIGS.6F-6G). Hpdl loss and 4-HMA rescue did not affect the F/I curves of cerebellar Purkinje cells (FIGS. 6C-6D).
  • Hpdl -/- mice are comparable to Hpdl +/- mice following 4-HMA treatment
  • 4-HMA treatment improves the neurological symptoms and metabolic physiology of Hpdl -/- mice
  • Hpdl -/- mice treated with 4-HMA had decreased gait periodicity (FIG.3C), but had identical performance on the pole test and transverse beam tests of cerebellar function (FIGS. 3D-3E). Both female and male Hpdl +/- mice and Hpdl -/- mice treated with 4-HMA had decreased forelimb grip strength relative to Hpdl +/+ mice, but did not have differences when the strength of all limbs was measured (FIG. 3F; FIGS. 6G, 6J). We did not observe differences in Rotarod latency between Hpdl +/+ mice, Hpdl +/- mice, and Hpdl -/- mice treated with 4-HMA (FIG. 6K).
  • non-neuronal symptoms of primary CoQ 10 deficiencies can respond to CoQ 10 or short- chain CoQ supplementation 41,42 , consistent with at least some bioavailability of CoQ10 to non- CNS organs.
  • 4-HMA or 4-HB supplementation may be of benefit in patients with HPDL variants that cause loss of HPDL function, or who have other defects in CoQ 10 headgroup synthesis. Because patients with HPDL variants appear normal at birth 19-26 , loss of HPDL function or other CoQ10 headgroup synthesis deficiencies ideally would be identified by newborn screening for reduced plasma 4-HMA, as we observed in our patients, or by sequencing so that supplementation with CoQ 10 headgroup intermediates can begin before symptoms develop.
  • Hpdl knockout does not significantly inhibit cellular development and that 4-HMA treatment accelerates maturation of Hpdl -/- Purkinje cells at P8-10.
  • 4-HMA treatment accelerates maturation of Hpdl -/- Purkinje cells at P8-10.
  • the electrophysiological characteristics of Hpdl +/+ , Hpdl +/- , and Purkinje cells from 4-HMA-treated Hpdl -/- pups have indistinguishable electrophysiological properties. 43 309005815v2 Attorney Docket No.: 243735.000414
  • Purkinje cell death induced by Hpdl loss would lead to loss of Purkinje function and cell axonal guidance signals, which may alter migration of granule cells from the EGL to the IGL.
  • HPDL loss may contribute to decreased numbers of cerebellar granule cells in the EGL, which reduces the population of cerebellar granule cells available to enter the IGL and form synapses with Purkinje cells and mossy fibers. The failure of these latter neurons to find their targets would lead to degeneration and the neurodevelopmental and neurodegenerative phenotypes that we observe in Hpdl -/- mice and patients with HPDL variants.
  • 4-HMA rescue substantially improves the overall survival of Hpdl -/- mice, but 4-HMA- treated Hpdl -/- mice have grip strength and weight comparable to Hpdl +/- mice.
  • the partial rescue of neurological phenotypes by 4-HMA could be due to inadequate dosing of 4-HMA or inability to import sufficient 4-HMA for CoQ10 synthesis. Alternately, inadequate production of 4-HMA during the late stages of embryogenesis, when granule cells start proliferating 46 , or peripheral nervous system defects could be responsible for these residual symptoms.
  • a proposed treatment is administration of 4-HB as an oral solution at a concentration of 5 mg/mL in water.
  • An example NEDSWMA patient might weigh approximately 30 kg. Said patient will be treated initially with 1 mg/kg 4-hydroxybenzoate (30 mg), corresponding roughly to the HED of the effective dose of 10 mg/kg studied in mice. If this dose is tolerated, the dose will increase to 10 mg/kg (300 mg) on the second day.
  • the dose will increase to 33 mg/kg (1000 mg) on the third day. If this dose is tolerated, the dose will increase to 100 mg/kg (3,000 mg) on the fourth day. This dose will be administered over 30-60 minutes if necessary to enable full dosing (the 3,000 mg dose will be equivalent to 600 ml of 4-HB DP solution at 5 mg/kg). The duration of dosing could be from 30 years to months or years, or potentially lifelong treatment.
  • a patient’s weight Prior to treatment, at days 3, 6, 15, and 30 after the first dose of 4-HB, and at 3, 6, 9, and 12 months after the end of the study, a patient’s weight will be measured, carry out neurological exams, and collect urine for organic acid analysis (malate, fumarate, lactate and pyruvate), a measure of mitochondrial disease (8). Also, pastic paraplegia rating scale (9), timed 10-meter walk test (10), 9-hole peg test (11), and the modified Ashworth scale (12) will be used to measure a patient’s neurological outcomes prior to, during, and after treatment. Brain and spine MRI/MRS, and video recording of the clinical exam will also be performed.
  • 4-HB is a natural mammalian metabolite. 4-HB is also the primary product of paraben catabolism in mammalians.
  • Parabens are simple esters of 4-HB widely used a food additives and 45 309005815v2 Attorney Docket No.: 243735.000414 preservatives and classified by the FDA as Generally Recognized as Safe (GRAS) (13). 4-HB is also found in high concentrations in natural foods (14-16). Based on this, acute toxicities are not anticipated from the proposed 4-HB treatment.
  • 4-Hydroxybenzoate has been tested in mice at doses of up to 500 mg/kg without observable toxicity. Toxicity would most likely be esophagitis or gastritis following administration of 4-hydroxybenzoic acid, as it has a pH of 4 in water (comparable to orange juice, which has a pH of 3.5).
  • a patient will be treated with aluminum hydroxide/magnesium hydroxide (Maalox/Mylanta), or with sucrose/calcium carbonate. If other toxicities are observed, the dose will be reduced by 20% and treatment will continue. If toxicity is observed a second time, the dose will be reduced by an additional 20%. If toxicity is observed after this point, the dose will be reduced to 1000 mg/day. If toxicity is observed after this point, the dose will be reduced to 300 mg/day. If toxicity is observed after this point, treatment will be discontinued.
  • the drug product to be used to treat a patient is 4-hydroxybenzoic acid in the form of white power prepared as a monophasic solution in water for oral use.
  • 4-HMA is converted to 4-hydroxybenzoic acid (4- HB).4-HB is the immediate precursor of the headgroup of Coenzyme Q10 (CoQ10), a lipophilic antioxidant critical for control of reactive oxygen species in biological membranes and for activity of the mitochondrial electron transport chain (FIG.10) (reviewed in(5).
  • CoQ10 Coenzyme Q10
  • FIG.10 mitochondrial electron transport chain
  • Biallelic HPDL variants cause a disease called NEDSWMA (Neurodevelopmental disorder with spastic paresis and brain white matter abnormalities; OMIM 619026) (1-4). This is a progressive, uniformly lethal pediatric encephalopathy. Patients with NEDSWMA present in childhood with progressive spasticity and neurodevelopmental delay.
  • spastic paraplegia-83 Patients with non-truncating HPDL variants present with a milder form of spastic paraplegia called spastic paraplegia-83 (OMIM 619027). 48 309005815v2 Attorney Docket No.: 243735.000414 [00216]
  • 4-HB the immediate precursor of the CoQ10 headgroup, should enter the brain and be incorporated into Coenzyme Q.
  • 4-HB is not detectable in plasma, but 4-HMA is detectable in the plasma of mice and patients.
  • Hpdl -/- mice have lower plasma levels of 4-HMA than wild-type mice (FIG.1E). Both 4- HMA and 4-HB at 10 mg/kg, dosed orally once daily, improve the survival of Hpdl -/- mice from 0% at 15 days to >90% at 300 days (FIG.1F). CoQ10 treatment does not improve the survival of mice lacking Hpdl (FIG. 1F).
  • Hpdl -/- mice must be treated with at least 10 mg/kg 4-HMA to improve their overall survival (FIG. 1F).
  • Hpdl -/- mice have cerebellar atrophy with Purkinje cell vacuolization and do not form the internal granular layer (IGL) of the mature cerebellum (FIG. 2C, panels C, G, K). These developmental defects are restored to near wild-type appearance by 4- HMA treatment (FIG.2C, panels D, H, L).
  • 4-HMA and 4-HB enter the brains of Hpdl -/- mice and account for half of the CoQ9 (the mouse equivalent of human CoQ10) synthesized in the brain (FIG.1H).
  • the 4-HB used for these studies came from a different source than the data in FIG.3A, and enabled all treated mice to survive to postnatal day 20, the time of sacrifice.
  • 4-HB would be administered as a suspension at a concentration of >10 mg/m, or as a pill, a lozenge, or a capsule. Consideration would need to be made for administration of this compound to neonates and infants who present with the more severe form of HPDL encephalopathy.
  • 4-HB will be prepared as a monophasic solution in water for oral use.4-HB will be added to distilled water to a concentration of 5 mg/mL with gentle stirring followed by sonication.
  • the solution will be vacuum filtered through a 0.2 ⁇ m PES membrane into a sterile bottle.
  • the solution has a sour taste and is palatable. Storage will be at 4 ⁇ C.
  • Formulated compound should be consumed within 24 hours of preparation or frozen at -20 ⁇ C immediately after formulation. [00227]
  • the purity and concentration of 4-HB will be measured by liquid chromatography-mass spectrometry.
  • the LC-MS method will use an Atlantis BEH Z-HILIC column mounted on a Dionex Ultimate 3000 UPLC coupled to a Thermo Q Exactive HF Orbitrap MS for detection.4- 50 309005815v2 Attorney Docket No.: 243735.000414 HB will be identified by retention time in comparison to unlabeled standards and a 13 C6-4-HB internal standard, MS1 accurate mass, and MS2 fragmentation. Concentration will be determined by comparison to a standard curve with a 13 C 6 -4-HB internal standard. Purity will be determined by measurement of the area under the 4-HB peak in comparison to the TIC. We will accept concentrations within 15% of the target concentration and purity of >80%, to account for high amounts of 13 C 6 -4-HB internal standard.
  • the final product will be packaged in a polypropylene bottle with tamper-evident packaging to be delivered to the patient.
  • Solutions can be made and frozen at -20 ⁇ C for at least a month without loss of efficacy in treating mice.4-HB is stable after storage at -20 ⁇ C in distilled water for 3 months (FIG.11B). Once the solution has been thawed, it must be brought to room temperature to ensure that all 4- HB has dissolved prior to use, and used within 24 hours.
  • Drug Components and Drug Product 51 309005815v2 Attorney Docket No.: 243735.000414 thawed, it will be mixed well to ensure that the 4-HB is dissolved and used with 24 hours.
  • LD 50 Mouse oral 2200 mg/kg (Lewis, R.J.
  • Parabens are simple ester precursors of 4- hydroxybenzoic acid (also known as para-hydroxybenzoic acid). Parabens are stable in air and resist hydrolysis in acidic medium and under conditions of sterilization. They have been used as preservatives in foods, cosmetics, and pharmaceutical additives for over five decades.
  • ⁇ Methyl and propyl paraben have been affirmed as Generally Recognized as Safe (GRAS) for direct addition to food at concentrations up to 0.1% and by prior sanction for indirect addition via packaging materials.
  • 52 309005815v2 Attorney Docket No.: 243735.000414
  • Methyl-, propyl- and butyl-paraben have been approved as synthetic flavoring substances and adjuvants for addition to beverages at minimum quantity, in amounts not to exceed 20 ppm.
  • ⁇ Methyl-, propyl- and butyl-paraben can also be used as direct food additives for use as preservatives in synthetic flavoring substances and adjuvants.
  • mice, rat, rabbit, and dog models showed that parabens are practically non-toxic by various routes of administration. Toxicities for these compounds are >1 g/L in large animal models.
  • a summary of acute toxicity data is provided in the Table 2. Table 2. Acute oral toxicity of parabens in mice, rats, rabbits, and dogs. lethal assay, and host-mediated assay indicated that parabens are not genotoxic.
  • mice were treated with topical 100 mg/kg 4-HMA in water. 4-HMA was applied directly to the skin using Q-tip every other day (week 5-week 12). Regrowth of hair in shaved 90-week-old-mice following treatment was observed (FIG.14). [00246] 90-Week-old mice (JAX C57/BL6 mice) were shaved and the shaved area was treated topically with 4-HMA (no systemic 4-HMA was provided).

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Abstract

La présente divulgation concerne une méthode de traitement d'une maladie ou d'un trouble choisi dans le groupe constitué par une maladie cardiaque, une maladie neurodégénérative, une migraine, une maladie du développement neurologique, une infertilité, une affection pulmonaire, une maladie musculaire, une maladie hépatique, une maladie pancréatique, une maladie buccale, une maladie ophtalmique, une maladie auditive, des maladies associées à la grossesse, des maladies associées à la prématurité, des troubles du vieillissement, des troubles du mouvement, une maladie infectieuse et toute maladie dans laquelle le coenzyme Q décline, chez un sujet en ayant besoin, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'acide 4-hydroxymandélique (4-HMA), de 4-hydroxybenzoate (4-HB) ou d'un composé de formule (I) ; où R1, R2, R3 et R4 sont tels que décrits dans la description. La présente invention a également pour objet un procédé d'amélioration de la cicatrisation chez un sujet et une méthode de traitement d'un trouble du développement neurologique avec une parésie spastique et des anomalies de la matière blanche cérébrale.
PCT/US2025/020495 2024-03-19 2025-03-19 Traitement par acide 4-hydroxybenzoïque pour augmenter la production de coq10 Pending WO2025199182A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110212913A1 (en) * 2008-10-31 2011-09-01 Provexis Natural Products Limited Therapeutic compositions comprising phenolic acids for treating conditions related to inappropriate platelet aggregation
US20110229554A1 (en) * 2010-03-12 2011-09-22 Niven Rajin Narain INTRAVENOUS FORMULATIONS OF COENZYME Q10 (CoQ10) AND METHODS OF USE THEREOF
CN110982771A (zh) * 2019-12-26 2020-04-10 江南大学 一种合成对羟基扁桃酸的方法
WO2022159473A1 (fr) * 2021-01-20 2022-07-28 New York University Méthodes et compositions pour le traitement de maladies ou de troubles liés à une protéine fonctionnant comme la 4-hydroxyphénylpyruvate dioxygénase (hpdl)
WO2023168053A2 (fr) * 2022-03-03 2023-09-07 New York University Inhibiteurs de hpdl et leurs utilisations

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110212913A1 (en) * 2008-10-31 2011-09-01 Provexis Natural Products Limited Therapeutic compositions comprising phenolic acids for treating conditions related to inappropriate platelet aggregation
US20110229554A1 (en) * 2010-03-12 2011-09-22 Niven Rajin Narain INTRAVENOUS FORMULATIONS OF COENZYME Q10 (CoQ10) AND METHODS OF USE THEREOF
CN110982771A (zh) * 2019-12-26 2020-04-10 江南大学 一种合成对羟基扁桃酸的方法
WO2022159473A1 (fr) * 2021-01-20 2022-07-28 New York University Méthodes et compositions pour le traitement de maladies ou de troubles liés à une protéine fonctionnant comme la 4-hydroxyphénylpyruvate dioxygénase (hpdl)
WO2023168053A2 (fr) * 2022-03-03 2023-09-07 New York University Inhibiteurs de hpdl et leurs utilisations

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