WO2025031475A1 - Procédé et médicament pour le traitement de l'endométriose - Google Patents

Procédé et médicament pour le traitement de l'endométriose Download PDF

Info

Publication number
WO2025031475A1
WO2025031475A1 PCT/CN2024/110958 CN2024110958W WO2025031475A1 WO 2025031475 A1 WO2025031475 A1 WO 2025031475A1 CN 2024110958 W CN2024110958 W CN 2024110958W WO 2025031475 A1 WO2025031475 A1 WO 2025031475A1
Authority
WO
WIPO (PCT)
Prior art keywords
s1pr1
endometriosis
bms
antagonist
medicament
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2024/110958
Other languages
English (en)
Inventor
Feng Ren
Aleksandrs Zavoronkovs
Wing Frank PUN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
InSilico Medicine IP Ltd
Original Assignee
InSilico Medicine IP Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by InSilico Medicine IP Ltd filed Critical InSilico Medicine IP Ltd
Publication of WO2025031475A1 publication Critical patent/WO2025031475A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • 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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines

Definitions

  • the present invention relates to the field of medicine, in particular, to a method for treating endometriosis.
  • Endometriosis is a chronic inflammatory gynecological disease characterized by the presence of ectopic endometrial glands and stroma, predominantly on the pelvic peritoneum, ovaries and the rectovaginal septum. About 5 -15%of women at reproductive age are estimated to suffer from endometriosis worldwide (PMID: 27159755) , and the prevalence can reach 35 -80%in women with pain and/or infertility (PMID: 32212520, 33640070) .
  • endometriosis is a systemic disease that alters cardiovascular, neurological, metabolic, and immune functions (PMID: 33640070) .
  • Patients may have increased risks of developing several chronic diseases, such as adenomyosis (PMID: 24532217) , ovarian cancer (PMID: 28240000) and autoimmune diseases (PMID: 31260048) .
  • AI artificial intelligence
  • PandaOmics to identify S1PR1 as a repurposing candidate for treating endometriosis.
  • the purpose of the present invention is to provide a therapy or a medicament for the treatment of endometriosis.
  • One aspect of the present invention provides a method for treating endometriosis in a subject in need thereof, comprising administering to the subject an effective amount of a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist.
  • S1PR1 sphingosine-1-phosphate receptor 1
  • the S1PR1 antagonist is one or more selected from the group consisting of Ponesimod, Ozanimod, Siponimod, Fingolimod, Etrasimod, Cenerimod, Mocravimod dihydrochloride, Amiselimod hydrocholoride, CBP-307, TT-01688-CL, Vibozilimod, Icanbelimod, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, Ceralifimod, PF-04629991 and a derivative thereof.
  • Another aspect of the present invention provides use of a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist in manufacture of a medicament for treating endometriosis.
  • S1PR1 sphingosine-1-phosphate receptor 1
  • the S1PR1 antagonist is one or more selected from the group consisting of Ponesimod, Ozanimod, Siponimod, Fingolimod, Etrasimod, Cenerimod, Mocravimod dihydrochloride, Amiselimod hydrocholoride, CBP-307, TT-01688-CL, Vibozilimod, Icanbelimod, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, Ceralifimod, PF-04629991 and a derivative thereof.
  • Another aspect of the present invention provides a medicament for use in treatment of endometriosis, wherein the medicament comprises a sphingosine-1-phosphate receptor 1 (S1PR1) antagonist.
  • S1PR1 sphingosine-1-phosphate receptor 1
  • the S1PR1 antagonist is one or more selected from the group consisting of Ponesimod, Ozanimod, Siponimod, Fingolimod, Etrasimod, Cenerimod, Mocravimod dihydrochloride, Amiselimod hydrocholoride, CBP-307, TT-01688-CL, Vibozilimod, Icanbelimod, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, Ceralifimod, PF-04629991 and a derivative thereof.
  • FIGs. 1A-1D show in silico analysis of the association between S1PR1 and endometriosis.
  • FIG. 1A Screenshot of the Target ID page of PandaOmics for endometriosis meta-analysis. S1PR1 was revealed as a druggable target for endometriosis. Data for gene expression, genetics, drugs, and text were available for the current analysis.
  • FIG. 1B Thirty-one uterine endometrial samples in GSE179640 were categorized into five groups: Ovarian endometriotic tissue, Peritoneal endometriotic tissue and its adjacent tissue, eutopic endometrium, and Control. Cells identified by scRNA-seq data were combined and then clustered into 18 clusters.
  • FIG. 1C The intensity of the expression of (FIG. 1C) S1PR1 in each cell cluster was displayed in the t-SNE plots.
  • FIG. 1D Dysregulated pathways associated with S1PR1 in endometriosis comparisons were displayed. Pathways were annotated by the Reactome database, and the degree of pathway dysregulation was determined by iPANDA algorithm. Bar colored in green and red indicates the number of comparisons with significant activation and inactivation of the corresponding pathway, respectively.
  • FIGs. 2A-2B show expression of S1PR1 in GSE203191.
  • FIG. 2A Based on disease diagnosis and symptom observation, 33 menstrual effluent samples were classified into three groups: Diagnosed, Symptomatic, and Control. Cells identified by scRNA-seq data from each group were combined and then clustered into 19 clusters. Expression intensities of (FIG. 2B) S1PR1 in the cell clusters were displayed in the t-SNE plots.
  • the term “comprise” , “include” , “contain” and variations of these terms, such as comprising, comprises and comprised, are not intended to exclude further members, components, integers or steps. These terms also encompass the meaning of “consist of” or “consisting of” .
  • the term “consist of” or “consisting of” is a particular embodiment of the term “comprise” , wherein any other non-stated member, component, integer or step is excluded.
  • endometriosis refers to a condition in which tissue containing typical endometrial granular and stromal elements occurs aberrantly in various locations in the pelvic cavity or some other area of the body (most commonly the peritoneal cavity) .
  • treat refers to alleviating, inhibiting and/or reversing the progress of a disease (such as endometriosis) .
  • the term “treating” is inclusive of any indicia of success in the treatment or amelioration of the disease, including any objective or subjective parameter such as abatement; remission; diminishing of symptoms or making the injury, pathology or condition more tolerable to the subject; delaying or slowing in the rate of progression, etc.
  • Measurement of the treatment or amelioration may be based on, e.g., the results of a physical examination, a pathological test and/or a diagnostic test as known in the art.
  • Treating may also refer to reducing the incidence or onset of a disease, or a recurrence thereof (such as a lengthening in time of remission) , as compared to that which would occur in the absence of the measure taken. Clinically, such a treatment can also be called prevention.
  • active agent refers to a pharmaceutically active chemical that provides some pharmacologic effect and is used for treating or preventing a disease, such as endometriosis.
  • inhibitor and “antagonist” , as used herein, can be used interchangeably and refer to any molecule that partially or fully blocks or inhibits an activity of a target (such as the protein used as a target in the present invention) .
  • derivatives of a compound refers to any pharmaceutically acceptable molecule that is derived from (i.e., structurally related to) the compound and has similar or substantially the same activity as the compound, which upon administration to a subject is capable of providing (directly or indirectly) a compound of the active agent or an active metabolite thereof.
  • the derivatives include, but are not limited to, pharmaceutically acceptable salt, hydrate, solvate, prodrug or metabolite.
  • pharmaceutically acceptable salt refers to a relatively nontoxic, inorganic or organic acid salt of a compound of the invention. These salts may be prepared in situ during the final isolation and purification of the compounds or by reacting the purified compound in its free form separately with a suitable organic or inorganic acid and isolating the salt thus formed.
  • Representative acid salts include, but are not limited to, acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tanna
  • solvate refers to a complex of variable stoichiometry formed by a solute (e.g., the active agent of the present invention) and a solvent.
  • a solute e.g., the active agent of the present invention
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • prodrug of a compound refers to a precursor, which when administered to a biological system, generates said compound as a result.
  • prodrugs can have the structure X-drug wherein X is an inert carrier moiety and drug is the active compound,
  • metabolite of a compound refers to a molecule which results from a modification or processing of the compound after administration to a subject.
  • the term “metabolite” may designate a modified or processed drug that retains at least part of the activity of the parent compound.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of a subject without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable carrier refers to any carrier that has substantially no long term or permanent detrimental effect when administered to a subject, such as a stabilizer, diluent, additive, auxiliary, excipient and the like.
  • “Pharmaceutically acceptable carrier” should be a pharmaceutically inert material that has substantially no biological activity and constitutes a substantial part of the formulation.
  • subject refers to any organism to which the active agent of the composition of the present invention may be administered, e.g., for experimental, diagnostic, prophylactic, and/or therapeutic purposes.
  • Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates such as chimpanzees and other apes and monkey species, and humans) .
  • the subject may be a mammal, particularly a human, including a male or female, and including a neonatal, infant, juvenile, adolescent, adult or geriatric, and further is inclusive of various races and ethnicities.
  • terapéuticaally effective dose or “effective dose” , as used herein, which can be used interchangeably with "therapeutically effective amount” or “effective amount” , refers to an amount that is effective for treating a disease (such as endometriosis) as noted through clinical testing and evaluation, patient observation, and/or the like.
  • An “effective amount” can further designate an amount that causes a detectable change in biological or chemical activity. The detectable changes may be detected and/or further quantified by one skilled in the art for the relevant mechanism or process.
  • an "effective amount” can designate an amount that maintains a desired physiological state, i.e., reduces or prevents significant decline and/or promotes improvement in the condition.
  • unit dosage form refers to physically discrete units (such as capsules, tablets, or loaded syringe cylinders) suitable as unitary dosages for a subject, each unit containing a predetermined quantity of active agent calculated to produce the desired therapeutic effect, in association with the required pharmaceutical carrier.
  • unit dose refers to a dose of a substance (such as an active agent of the present invention) in a unit dosage form.
  • S1PR1 sphingosine-1-phosphate receptor 1
  • An antagonist or agonist of the target may be used to treat endometriosis.
  • Sphingosine-1-phosphate receptor 1 S1P receptor 1 or S1PR1
  • S1PR1 also known as endothelial differentiation gene 1 (EDG1)
  • EDG1 endothelial differentiation gene 1
  • S1PR1 is a protein that in humans is encoded by the S1PR1 gene.
  • S1PR1 is a G-protein-coupled receptor which binds the bioactive signaling molecule sphingosine 1-phosphate (S1P) .
  • S1PR1 belongs to a sphingosine-1-phosphate receptor subfamily comprising five members (S1PR1-5) .
  • S1PR1 was originally identified as an abundant transcript in endothelial cells and it has an important role in regulating endothelial cell cytoskeletal structure, migration, capillary-like network formation and vascular maturation. In addition, S1PR1 signaling is important in the regulation of lymphocyte maturation, migration and trafficking.
  • the active agent used to treat endometriosis can be any one selected from the group consisting of S1PR1 antagonists, including but not limited to Ponesimod, Ozanimod, Siponimod, Fingolimod, Etrasimod, Cenerimod, Mocravimod dihydrochloride, Amiselimod hydrocholoride, CBP-307, TT-01688-CL, Vibozilimod, Icanbelimod, SCD-044, BMS-986166, BMS-986104, CP-1050, BMS-520, BMS-542, Ceralifimod, PF-04629991 and a derivative thereof.
  • S1PR1 antagonists including but not limited to Ponesimod, Ozanimod, Siponimod, Fingolimod, Etrasimod, Cenerimod, Mocravimod dihydrochloride, Amiselimod hydrocholoride, CBP-307, TT-01688-CL, Vibozilimod, Icanbelimod, SCD-044, BMS-9
  • the amount of each of the active agents in a unit dosage form may be 1-1000mg, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15 , 16, 17, 18, 19, 20, 25, 30, 35, 40, 50, 60, 70, 75, 80, 90, 100, 110, 120, 125, 130, 140, 150, 160, 170, 175 , 180, 190, 200, 250, 300, 350, 400, 450, 500, 600, 700, 750, 800, 900, 1000mg or any range between any two of the above specific values.
  • Each of the active agent of the present invention may be administered to the subject via oral, buccal, sublingual, rectal, vaginal, parenteral, intradermal or intranasal or parenteral route.
  • the parenteral administration includes intravenous, intraperitoneal, intradermal, subcutaneous, intramuscular, intracranial, intrathecal, intratumoral, transdermal, transmucosal intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional or intracranial injection or infusion.
  • the active agent (s) as used herein may be formulated for administration in a pharmaceutical composition in accordance with known techniques. See, for example, Remington, The Science and Practice of Pharmacy (9th Ed. 1995) .
  • the active agent is typically admixed with, inter alia, a pharmaceutical acceptable carrier.
  • the carrier must, of course, be acceptable in the sense of being compatible with any other ingredients in the formulation and must not be deleterious to the patient.
  • the carrier may be a solid or a liquid, or both, and is preferably formulated with the compound as a unit-dose formulation, for example, a tablet, which may contain from 0.01%or 0.5%to 95%or 99%by weight of the active agent.
  • compositions of the invention may be prepared by any of the well-known techniques of pharmacy comprising admixing the components, optionally including one or more accessory ingredients and/or excipients.
  • any of the compositions, carriers, accessory ingredients excipients and/or the formulations of the invention comprise ingredients that are from either natural or non-natural sources.
  • any component of the compositions, carriers, accessory ingredients, excipients and/or the formulations of the invention may be provided in a sterile form.
  • a sterile carrier include endotoxin-free water or pyrogen-free water.
  • the pharmaceutical composition of the invention is provided as part of a sterile composition/formulation comprising an active agent of the invention and a pharmaceutically acceptable carrier and/or excipient.
  • Dosage forms suitable for the oral administration include tablet, capsule, powder, pill, granule, suspension, solution or preconcentrate of solution, emulsion or preconcentrates of emulsion.
  • Pharmaceutical acceptable carriers that can be used in an oral dosage form include water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like. Carriers such as starches, sugars, microcrystalline cellulose, diluents, filler, glidants, granulating agents, lubricants, binders, stabilizers, disintegrating agents and the like can be used to prepare an oral solid preparation such as powder, capsule or tablet.
  • the diluent includes, but not limited to, microcrystalline cellulose, mannitol, powdered sugar, compressible sugar, dextran, dextrin, spinose, lactose, cellulose powder, sorbitol, sucrose and Talc powder or a combination thereof.
  • the diluent may be 5%to 90%based on the total weight of the oral composition, preferably 10%to 80%, 20%-70%, 30%-60%, 40%-50%.
  • the disintegrating agent includes, but not limited to, cellulose, alginate, gum, cross-linked polymer, such as cross-linked polyvinylpyrrolidone or crospovidone, croscarmellose sodium, croscarmellose calcium, soybean polysaccharide, sodium starch glycolate, guar gum or any combination thereof.
  • the disintegrating agent may be present in an amount of about 1%to 15%, preferably 2%to 10%, based on the total weight of the oral composition.
  • the binder includes, but not limited to, starch, cellulose or derivatives thereof, such as microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methyl cellulose, sucrose, dextrose, corn syrup, polysaccharide, gelatin or any combination thereof.
  • the binder may be present in an amount of 0.01 to 10%, preferably 1%to 10%, based on the total weight of the composition.
  • the glidant includes, but not limited to, colloidal silicon dioxide, magnesium trisilicate, cellulose powder, talc powder or a combination thereof can be selected.
  • the glidant may be present in an amount of 0.1%to 10%, preferably 0.1%to 0.5%, based on the total weight of the composition.
  • Dosage forms can be in the form, e.g., of tablets or capsules, and the effective dose may be provided in one or more tablets, capsules or the like, and be provided once a day or throughout the day at intervals, e.g., of 4, 8 or 12 hours.
  • Tablets or capsules could contain, e.g., 10, 25, 50, 75, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1,000, 1, 100, or 1, 250 mg of the active agent.
  • administration to a human subject of the active agent of the present invention may comprise a daily dosage in the range of 100-1, 250, 150-1,000, 200-800, or 250-750 mg, which daily dosage can be administered either once a day in its entirety or fractions of which are administered throughout the day in intervals.
  • Liquid formulations can also be prepared so that any dosage may readily and conveniently be dispensed.
  • Parenteral dosage forms are preferably sterile or capable of being sterilized prior to administration to a subject.
  • Examples of parenteral dosage forms include, but are not limited to, solutions ready for injection, dry products ready to be dissolved or suspended in a pharmaceutically acceptable carrier for injection, suspensions ready for injection, and emulsions.
  • Suitable carriers that can be used to provide parenteral dosage forms provided herein include, but are not limited to: water for injection; aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection; water-miscible carriers such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol; and non-aqueous carriers such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.
  • aqueous vehicles such as, but not limited to, sodium chloride injection, Ringer's injection, dextrose injection
  • water-miscible carriers such as, but not limited to, ethyl alcohol, polyethylene glycol, and polypropylene glycol
  • non-aqueous carriers such as, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil,
  • cyclodextrin and its derivatives can be used to increase the solubility of an active agent of the present invention.
  • a therapeutically effective dose may be determined by a physician, according to such as the type, stage and/or severity of the disease, the condition, age, body weight, sex and response of the subject to be treated, as well as the route of administration.
  • a therapeutically effective amount is an amount such that when administered to a subject is sufficient to achieve a plasma concentration of from about 0.01 ⁇ g/ml to about 100 ⁇ g/ml, from about 0.1 ⁇ g/ml to about 10 ⁇ g/ml, from about 1 ⁇ g/ml to about 5 ⁇ g/ml.
  • the therapeutically effective amount of each of the active agents generally may be in the range of about 0.5 to about 250 mg/kg, about 1 to about 250 mg/kg, about 2 to about 200 mg/kg, about 3 to about 120 mg/kg, about 5 to about 250 mg/kg, about 10 to about 200 mg/kg, or about 20 to about 120 mg/kg for each active agent of the present invention.
  • the therapeutically effective amount may be 0.5mg/kg, 1mg/kg, 2mg/kg, 3mg/kg, 4mg/kg, 5mg/kg, 6mg/kg, 8mg/kg, 10mg/kg, 20mg/kg, 25mg/kg, 40mg/kg, 50mg /kg, 60mg/kg, 75mg/kg, 100mg/kg, 120mg/kg, 150mg/kg, 175mg/kg, 200mg/kg, 225mg/kg, 250mg/kg or 300mg/kg.
  • Each of the active agents of the present invention may be administered once or twice one day; or once every 2, 3, 4, 5, 6, 7, 8, 9 or 10 days or once every 1, 2 or 3 weeks.
  • each of the active agents of the present invention may be administered in a five times weekly scheme. In the five times weekly scheme, the administration may be done on five consecutive days (once daily) followed by two consecutive days off.
  • kit refers to a package and, as a rule, instruction for use.
  • An active agent or a pharmaceutical composition in a kit can be in any of a variety of forms suitable for distribution in a kit. Such forms can include a liquid, powder, tablet, suspension and the like. Two or more active agents may be provided in separate containers suitable for administration separately, or alternatively may be provided in a composition in a single container in the package.
  • the kit may contain an amount sufficient for one or more dosages of agents according to the treatment methods.
  • the instruction for use generally comprises a literal statement of how to treat a disease (such as ALS) with the agents in the kit.
  • combination or pharmaceutical composition of the present invention may include other therapeutic agents or therapies, such as biological therapeutic agents and/or chemotherapeutic agents in addition to the active agents of the present invention.
  • the method may include administration of other therapeutic agents or therapies, such as biological therapeutic agents and/or chemotherapeutic agents in addition to administration of the active agents of the present invention.
  • Other therapeutic agents or therapies may be administered simultaneously, separately or sequentially with the therapeutic agents of the present invention.
  • PandaOmics was a cloud-based target discovery platform with multiple deep learning models and AI algorithms incorporated in the target prioritization process. Twenty-three target prioritization models covering Omics, Text-based, Financial, and Key Opinion Leader (KOL) data were developed to predict the association between the target genes and a particular indication. Scores of each of the models are given in a normalized scale from zero to one, with higher scores corresponding to better target-disease association as predicted by the model. These models were validated using a Time Machine approach to confirm their abilities in target identification. Adjustable filters for druggability, tissue specificity, target family, and developmental status were also available to refine the target list.
  • KOL Key Opinion Leader
  • GSE203191 menstrual effluent samples were collected from 11 endometriosis (diagnosed) , 13 symptomatic (not diagnosed but with chronic endometriosis symptoms) , and 9 control subjects. Samples in GSE179640 were isolated from five regions: healthy uterine endometrium, eutopic endometrium from patients with endometriosis, ectopic endometriotic tissues from ovary and peritoneum, as well as tissue adjacent to the endometriotic lesion in the peritoneum.
  • sample data matrices generated by Cell Ranger were retrieved from the GEO database, and subject to gene and cell filtrations as well as cell cluster annotations as defined in the original paper (PMID: 36104692) .
  • GSE179640 the processed data that contains normalized expression, cell cluster annotations, sample metadata, as well as dimensionality reduction coordinates was readily provided by the authors and retrieved from https: //singlecell. jax. org/datasets/endometriosis-2022 . Differential gene expression between different cell clusters or different sample groups was calculated by Wilcoxon rank sum test using the log-normalized count data.
  • iPANDA Signaling pathway activation status was assessed using PandaOmics proprietary single network model iPANDA (PMID: 27848968) . With the combinational use of differential gene expression data and the degree of pathway topology decomposition, iPANDA robustly identified sets of biological relevant pathway signatures from the input data with significant noise reduction. iPANDA value of 1 and -1 indicated pathway activation and suppression, respectively. Hierarchical organization of signaling pathways were curated based on the Reactome database.
  • Endometriosis meta-analysis with 11 subtype and cycle nonspecific comparisons was utilized for target identification (Table 1) .
  • high confidence targets associated with the disease were screened based on the ranking calculated by PandaOmics, the consistency of dysregulated expression across comparisons included in the meta-analysis, statistical significance of the dysregulation, as well as literature support in driving endometriosis or with potential roles in the underlying mechanisms promoting endometriosis.
  • S1PR1 was ranked as the 223 th target in the meta-analysis, and scored at least 0.8 in four Omics AI score models, i.e. Network neighbors, Expression, Heterogenous graph walk and Matrix factorization (Fig. 1A) .
  • GSE179640 is composed of control samples collected from uterine endometrium, eutopic endometrium of patients, ectopic endometriotic lesions from peritoneum and ovary, and tissue adjacent to the endometriotic lesions in the peritoneum.
  • S1PR1 was specifically enriched in endothelial cells in GSE179640. It was significantly overexpressed in the endothelial cells and one of the myeloid cell clusters in the ovarian endometriosis samples. Its upregulation was also detected in the NK cells and a myeloid cell cluster in the peritoneal endometriosis lesions and adjacent tissue of the peritoneal endometriosis lesions, respectively (Fig. 1B and 1C) .
  • S1PR1 mainly contributed to immune regulatory pathways, by which most of them are prominently activated in endometriotic samples (Fig. 1D) .
  • Literature has demonstrated the pivotal role of S1PR1 and its ligand, sphingosine-1-phosphate (S1P) , in immune response.
  • Information of the associations between S1PR1 variants and traits was retrieved from GWAS Catalog, and half of the traits are immune-related. Loss-of-function of S1PR1 in mice is lethal.
  • S1PR1 Conditional mutations of S1PR1 drive severe phenotypic abnormalities in immune, cardiovascular, and neuronal systems (PMID: 22975327, 16314531, 12869509, 20584883, 21960637) .
  • Upregulation of S1PR1 has been reported in endometriosis (PMID: 30782093, 22277765) .
  • S1P increased the expression of IL-6 and proliferative ability of the endometriotic cells (PMID: 30782093) .
  • Inhibition of S1PR1 and S1PR3 suppressed S1P-induced endometriotic stromal cell proliferation (PMID: 30782093) .
  • S1P and its downstream pathway mediated the induction of expression of COX-2 and PGE2 production, two important mediators of inflammation (PMID: 12890694, 26994820) .
  • endometriosis is a chronic inflammatory disease and S1PR1 demonstrated a close linkage with endometriosis, targeting S1PR1 could be a therapeutic approach for endometriosis.
  • the launched agonists of S1PR1 -fingolimod, siponimod, ozanimod and ponesimod functionally antagonize the action of S1PR1, and are indicated for treating multiple sclerosis. Binding of these compounds to S1PR1 induces receptor internalization and degradation. In particular, ponesimod acts specifically on the S1PR1 receptor. Besides the launched ones, sixteen additional compounds have been designed to target S1PR1 and tested in various indicators, i.e.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Emergency Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Reproductive Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé et un médicament pour le traitement de l'endométriose chez une patiente en ayant besoin, comprenant l'administration à la patiente d'une quantité efficace d'un antagoniste du récepteur 1 de la sphingosine-1-phosphate (S1PR1).
PCT/CN2024/110958 2023-08-10 2024-08-09 Procédé et médicament pour le traitement de l'endométriose Pending WO2025031475A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CNPCT/CN2023/112244 2023-08-10
CN2023112244 2023-08-10

Publications (1)

Publication Number Publication Date
WO2025031475A1 true WO2025031475A1 (fr) 2025-02-13

Family

ID=94533642

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2024/110958 Pending WO2025031475A1 (fr) 2023-08-10 2024-08-09 Procédé et médicament pour le traitement de l'endométriose

Country Status (1)

Country Link
WO (1) WO2025031475A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180217154A1 (en) * 2015-07-21 2018-08-02 Saint Louis University Compositions and methods for diagnosing and treating endometriosis-related infertility
CN110536694A (zh) * 2017-04-20 2019-12-03 Atyr 医药公司 用于治疗肺部炎症的组合物和方法
CN111265504A (zh) * 2020-02-18 2020-06-12 浙江正熙生物医药有限公司 S1pr1拮抗剂在制备用于治疗流感病毒感染引起的细胞因子风暴的药物中的应用
EP4212156A1 (fr) * 2022-01-13 2023-07-19 Abivax Combinaison de 8-chloro-n-(4-(trifluorométhoxy)phényl)quinolin-2-amine et de ses dérivés avec un modulateur de récepteur de s1p

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180217154A1 (en) * 2015-07-21 2018-08-02 Saint Louis University Compositions and methods for diagnosing and treating endometriosis-related infertility
CN110536694A (zh) * 2017-04-20 2019-12-03 Atyr 医药公司 用于治疗肺部炎症的组合物和方法
CN111265504A (zh) * 2020-02-18 2020-06-12 浙江正熙生物医药有限公司 S1pr1拮抗剂在制备用于治疗流感病毒感染引起的细胞因子风暴的药物中的应用
EP4212156A1 (fr) * 2022-01-13 2023-07-19 Abivax Combinaison de 8-chloro-n-(4-(trifluorométhoxy)phényl)quinolin-2-amine et de ses dérivés avec un modulateur de récepteur de s1p

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
YOSHINO OSAMU, YAMADA-NOMOTO KAORI, KANO KUNIYUKI, ONO YOSUKE, KOBAYASHI MUTSUMI, ITO MASAMI, YONEDA SATOSHI, NAKASHIMA AKITOSHI, : "Sphingosine I Phosphate (S1P) Increased IL-6 Expression and Cell Growth in Endometriotic Cells", REPRODUCTIVE SCIENCES, SAGE PUBLICATIONS, INC., US, vol. 26, no. 11, 1 November 2019 (2019-11-01), US , pages 1460 - 1467, XP093272800, ISSN: 1933-7191, DOI: 10.1177/1933719119828112 *
ZHANG FENGRUI, LU YUAN: "The Sphingosine 1-Phosphate Axis: an Emerging Therapeutic Opportunity for Endometriosis", REPRODUCTIVE SCIENCES, SAGE PUBLICATIONS, INC., US, vol. 30, no. 7, 1 July 2023 (2023-07-01), US , pages 2040 - 2059, XP093272803, ISSN: 1933-7191, DOI: 10.1007/s43032-023-01167-2 *
ZHANG FENGRUI, PENG MINGYI, ZHENG XUFEN, WANG XIAOFANG, LIU XIAOXIAO, CHEN CHUN, LU YUAN: "Blocking sphingosine 1-phosphate receptor 1 with modulators reduces immune cells infiltration and alleviates endometriosis in mice", REPRODUCTIVE BIOMEDICINE ONLINE, ELSEVIER, AMSTERDAM, NL, vol. 47, no. 5, 1 November 2023 (2023-11-01), AMSTERDAM, NL , pages 103304, XP093272798, ISSN: 1472-6483, DOI: 10.1016/j.rbmo.2023.103304 *

Similar Documents

Publication Publication Date Title
AU2013258566B2 (en) Pyrazole derivative and use thereof for medical purposes
EP3694500A1 (fr) Traitement de troubles inflammatoires
KR102547164B1 (ko) 특정 환자 집단에서 신경퇴행성 장애를 치료하는 방법
JP2023516284A (ja) カンナビジオールの組成物および治療的使用
WO2017223433A1 (fr) Méthodes et compositions pour le traitement du cancer
Masuda et al. Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease
WO2025031477A1 (fr) Procédé et médicament pour le traitement de l'endométriose
Ding et al. Transcriptome signature analysis repurposes trifluoperazine for the treatment of fragile X syndrome in mouse model
Chen et al. Tetrahydroalstonine possesses protective potentials on palmitic acid stimulated SK-N-MC cells by suppression of Aβ1-42 and tau through regulation of PI3K/Akt signaling pathway
WO2025031474A1 (fr) Méthode et médicament pour le traitement de l'endométriose
CN122070145A (en) Methods and medicaments for the treatment of endometriosis
US20200121666A1 (en) Tau phosphorylation inhibitors and methods for treating or preventing alzheimer's disease
US20240197817A1 (en) Compositions for treating autoimmune, alloimmune, inflammatory, and mitochondrial conditions, and uses thereof
WO2023116671A1 (fr) Procédé et médicament pour le traitement de la sclérose latérale amyotrophique
JP2015505314A5 (fr)
CN110831590A (zh) 含有培马贝特的医药
US20220347135A1 (en) Methods of Treatment of Spontaneous Preterm Birth
WO2018192469A1 (fr) Inhibiteurs de fabp4 et méthodes de traitement de l'arthrite
JP7535786B2 (ja) 関節炎治療剤
CN112843065B (zh) 一种用于认知障碍的药物及其制备方法
JP7849841B2 (ja) リソソーム関連膜タンパク質標的化化合物及びその使用
US20260108483A1 (en) Methods and compositions for preventing the progression of diabetic retinopathy and related conditions
CN121313788A (zh) 天然环二肽在制备放射性口腔黏膜炎治疗制剂中的应用
Zhang et al. Effect of pregnancy on nitrofurantoin disposition in mice
WO2024012531A1 (fr) Utilisation d'un dérivé de pyridone

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24851119

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 2024851119

Country of ref document: EP

NENP Non-entry into the national phase

Ref country code: DE