WO2000061182A2 - Techniques et compositions pour le traitement et la prevention des maladies pulmonaires - Google Patents

Techniques et compositions pour le traitement et la prevention des maladies pulmonaires Download PDF

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Publication number
WO2000061182A2
WO2000061182A2 PCT/US2000/009494 US0009494W WO0061182A2 WO 2000061182 A2 WO2000061182 A2 WO 2000061182A2 US 0009494 W US0009494 W US 0009494W WO 0061182 A2 WO0061182 A2 WO 0061182A2
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specific
agonist
rarα
rarβ
rar
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WO2000061182A3 (fr
Inventor
Roshantha A. Chandraratna
Donald Massaro
Gloria Decarlo Massaro
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Allergan Sales LLC
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Allergan Sales LLC
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • This invention concerns the use of isotype-specific retinoic acid receptor (RAR) agonists for the inhibition of alveolar destruction and/or to promote the formation of alveoli in mammalian lung tissue deficient in adequate numbers of functional alveoli .
  • RAR retinoic acid receptor
  • the lung functions to provide an interface for the exchange of gases between blood and the atmosphere.
  • the agents of this exchange are numerous small sacs termed alveoli (in adult humans about 300,000,000 per lung) uhat provide a gas permeable-liquid impermeable barrier between the gas and liquid phases. Between the alveoli are numerous capillaries carrying deoxygenated blood to the lung from the tissues and oxygenated blood from the alveoli to the tissues .
  • the partial pressure of oxygen in the lungs is approximately 100 mm Hg at sea level; at this pressure the binding of oxygen by hemoglobin in the erythrocytes is favored.
  • the alveoli thus provide a means for presenting the oxygen to hemoglobin to permit the conversion of deoxyhemoglobin to hemoglobin. Because the exchange occurs at the surface of the gas/blood barrier, alveoli have evolved as a means for providing extremely high surface area in a compact overall area, thus maximizing possible gas exchange. Lack of adequate gas exchange would lead to disability, which could progress to death.
  • BPD bnrochiopulmonary dysplasia
  • emphysema a disease of prematurely born infants, and is characterized mainly by a failure of the infant to form a sufficient number of appropriately-sized alveoli.
  • Emphysema a disease of middle and advanced age, appears to be due to progressive proteinase-induced alveolar destruction.
  • alveoli formation is reasonably well understood from a gross developmental standpoint, and seems to be similar in rat, mouse, and human, the major species studied.
  • the process includes the subdivision (septation) of the saccules that constitute the gas-exchange region of the immature lung. Septation results in the formation of smaller, more numerous gas-exchange structures (alveoli) .
  • the timing of the onset and cessation of septation vary among species, but both onset and cessation are critical to the formation of alveoli of the size and number needed for adequate oxygenation.
  • the molecular basis of the initiation and cessation of alveoli formation are not as well understood as the structural events and timing accompanying alveoli development.
  • ATRA can have a multiplicity of physiological effects.
  • the retinoid receptors when bound by an appropriate ligand, are mediators of various life processes, including reproduction, metabolism, differentiation, hematopoiesis, and embryogenesis .
  • the therapeutic use of the pan- agonist ATRA may give rise to a variety of undesirable or even toxic side effects over time.
  • Figure 1A is a photomicrograph of a histological section of the lung of a 14-day old rat injected intraperitoneally daily from age 3 to 13 days with cottonseed oil (control) .
  • Figure IB is a photomicrograph of a histological section of the lung of a 14-day old rat injected intraperitoneally daily from age 3 to 13 days with an
  • the present invention is directed to methods and compositions for promoting the formation of alveoli in mammalian lung tissue.
  • the invention comprises a therapeutic method for inducing the formation of alveoli in mammalian lung tissue by administration of a composition comprising a therapeutically effective amount of an ligand that is an RAR ⁇ agonist and that does not have RAR agonist activity at all RAR isotypes.
  • the RAR ⁇ agonist has specific RAR modulating activity at the RAR ⁇ receptor, and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not specific to either the RAR ⁇ or the RAR ⁇ receptor.
  • the ligand is specific to RAR ⁇ isotypes.
  • a ligand is a retinoid.
  • KD disassociation constant
  • RAR the ligand concentration at which 50% of the target RAR receptors are co plexed with the ligand
  • RAR receptor at least 10 times, preferably at least 25 times, even more preferably at least 50 times, and most preferably at least 100 times greater than the KD for the binding of the same ligand to an RXR receptor. Determination of the KD at an RAR or RXR receptor for a given ligand is a routine matter.
  • agonist is meant a retinoid receptor ligand that will cause the activation of transcription at a gene having an appropriate retinoid receptor response element .
  • antagonist is meant a retinoid receptor ligand that will inhibit the activation of transcription by the retinoid receptor at a gene having an appropriate retinoid receptor response element in the presence of an agonist of the retinoid receptor.
  • inverse agonist is meant a retinoid receptor ligand that will inhibit the expression of transcription at a gene having an appropriate retinoid receptor response element beyond a basal expression level existing in the absence of an agonist of the retinoid receptor.
  • the invention is directed to therapeutic compositions for the treatment of an emphysemic mammal, or of a mammal suffering from bronchopulmonary dysplasia, comprising a therapeutically effective amount of an ligand that is an RAR ⁇ agonist and that does not have RAR agonist activity at all RAR isotypes .
  • the RAR ⁇ agonist has specific RAR modulating activity at the RAR ⁇ receptor, and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not specific to either the RAR ⁇ or the RAR ⁇ receptor.
  • the ligand is specific to RAR ⁇ isotypes.
  • a ligand is a retinoid.
  • the RAR ⁇ agonist may be used either as the only active ingredient in the composition, or in combination with one or more additional therapeutically active ingredient.
  • the additional therapeutically active ingredient is a retinoid; in a preferred aspect, an additional therapeutically active ingredient is another RAR-active ligand, for example, all- trans- retinoic acid.
  • RAR-active retinoid is meant that the retinoid has agonist, inhibitory, or inverse agonist (negative hormone) activity at an RAR receptor.
  • therapeutically effective amount is meant that the amount of the RAR-specific therapeutic agent is sufficient, either as the result of a single dose, or as the result of multiple doses over the term of therapy, to decrease the rate of alveolar destruction in an emphysemic mammal, or to promote the growth of alveolar septa in said mammal .
  • the present invention is directed to compositions and methods for the treatment or prevention of alveolar destruction and/or to promote the formation of alveoli is mammalian lungs deficient in adequate numbers of functional alveoli.
  • Such methods and compositions involve RAR-active retinoids, therapeutic compositions containing such agents, and methods for their use.
  • the retinoid receptors are part of the steriod/thyroid/vitamin D superfa ily of nuclear receptors .
  • the retinoid receptors include the retinoic acid receptors (RAR) and the retinoid X receptor (RXR) .
  • the RAR and RXR receptors are single chain polypeptides containing a number of structural domains in common: a ligand binding domain, a sequence-specific DNA binding domain, and a leucine zipper motif. In the presence of ligand, the single RAR or RXR chains can, by virtue of the leucine zipper, form dimers .
  • the RAR chain is believed to exist in vivo exclusively as an RAR/RXR heterodimer .
  • RXR may form heterodi ers with RAR or other members of the superfamily, such as the vitamin D receptor and the thyroid receptor .
  • Retinoid receptor dimers are effective transcription factors regulating gene transcription by binding to retinoic acid response elements (RAREs) or retinoid X response elements (RXREs) present in (or near) the promoters of retinoid responsive genes, or by negatively regulating the enhancer functions of other transcription factors.
  • RAREs retinoic acid response elements
  • RXREs retinoid X response elements
  • RAR isotypes include RAR ⁇ , RAR ⁇ , and RAR ⁇
  • described RXR isotypes include RAR ⁇ , RAR ⁇ , and RAR ⁇ .
  • each receptor class these isotypes have sequence ho ology, but are encoded by different genes.
  • Within each isotype several isoforms have been described; these isoforms differ in their N terminals and are generated by alternative splicing and/or differential usage of more than one promoter. See e.g., Nagpal & Chandraratna, Current Pharm . Design 2:295-316 (1996) and Mangelsdorf et al . , The Retinoid Receptors in The Retinoids : Biology, Chemistry and Medicine Ch. 8 (2d ed. Sporn et al . eds . 1994) , both of which are hereby incorporated by reference herein.
  • RAR e.g., ATRA
  • RXR e.g., TTNB
  • KD disassociation constant
  • KD disassociation constant for the binding of the ligand to a given target receptor or receptor isotype or isoform is at least 10 times lower than the KD value for the ligand and a non- target receptor or receptor isotype or isoform.
  • KD is defined as the concentration of ligand at which 50% of the receptors are ligand bound. Even more preferably, KD is at least 25 times lower for the target receptor than for untargeted receptors. Most preferably, KD is at least 50, or at least 100, times lower for the target receptor than for untargeted receptors .
  • compositions for the treatment or prevention of alveolar destruction and/or the promotion of alveolar formation in a mammal comprise a ligand that is an RAR ⁇ agonist and that does not have RAR agonist activity at all RAR isotypes.
  • the RAR ⁇ agonist has specific RAR modulating activity at the RAR ⁇ receptor, and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not specific to either the RAR ⁇ or the RAR ⁇ receptor.
  • the ligand is specific to RAR ⁇ isotypes.
  • a ligand is a retinoid.
  • Alveolar destruction may be the result of a pathological condition such as emphysema. Treatment to promote alveolar formation may be in response to a condition such as bronchopulmonary dysplasia (BPD) .
  • BPD bronchopulmonary dysplasia
  • Another aspect of the invention is methods for the treatment of treatment or prevention of alveolar destruction and/or the promotion of alveolar formation in a mammal, comprising administering a therapeutic amount of a composition comprising a retinoid receptor ligand that is an RAR ⁇ agonist and that does not have RAR agonist activity at all RAR isotypes.
  • the RAR ⁇ agonist has specific RAR modulating activity at the RAR ⁇ receptor, and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not an agonist of the RAR ⁇ receptor.
  • the RAR ⁇ receptor agonist has specific RAR modulating activity at the RAR ⁇ receptor and is not specific to either the RAR ⁇ or the RAR ⁇ receptor.
  • the ligand is specific to RAR ⁇ isotypes.
  • a ligand is a retinoid.
  • compositions of the present invention can be administered in any therapeutically effective manner or form, and in conjunction with any pharmacologically effective vehicle.
  • the compositions of the invention may be administered in the form of an inhalant as a powdered or liquid aerosol .
  • Such a formulation may comprise the active agent solubilized in a micronized hydrophobic/hydrophilic emulsion.
  • Such compositions are well known to those of skill in the art .
  • the compositions may be administered systemically, such as intravenously by infusion, or by intraperitoneal injection.
  • compositions of the present invention are well known to those of skill in the art, and therefore formulation of the compositions of the present invention with such solutions would be well within the ability of such a person with the disclosure of this application.
  • administration of drugs by intraperitoneal injection is well known, and pharmacological vehicles are well known.
  • Patent 5,455,265 incorporated by reference herein, describes a chimeric receptor transactivation assay which tests for RAR-agonist activity in the RAR- ⁇
  • this assay employs chimeric proteins containing an RAR ligand-binding domain and a heterologous polypeptide segment having the ability to bind to a response element (RE) , in turn facilitating transcription of a specific, measurable target gene, such as chloramphenicol acetyltransferase (CAT) .
  • a specific, measurable target gene such as chloramphenicol acetyltransferase (CAT) .
  • CAT chloramphenicol acetyltransferase
  • Variation of this transactivation assay permits testing ligands as RAR antagonists, or antagonists of a given target isotype.
  • a competitive assay involving the use of a stimulatory concentration of a known agonist of a given receptor (for example, ATRA is known to be an agonist of all RAR isotypes) , and measuring the reduction in a reporter gene expression
  • membrane preparations containing cloned retinoid receptors can be used, and the receptors loaded with a known radiolabeled ligand. The release of radioactivity from these preparations as a function of test compound concentration can be determined. The lower the Kd for a given ligand, the more likely the ligand will be effective as a modulator of receptor activity. Further disclosure is available in, e.g., U.S. Patent No. 5,776,699, previously incorporated by reference herein.
  • alveolus formation can continue up to the age of 20.
  • the rate of increase in specific lung volume (expressed as cm 3 /100 g body weight) in rats is greatest within the first 10 days following birth, after which it increases at a less steep rate.
  • the lung's efficiency is determined not merely by the volume of air that can be contained in the lung, but by the alveolar surface area, which is a function of tissue growth within the lung. Burri et al., Anat . Rec . 178:711-730 (1973) and Burri, Anat. Rec .
  • RAR ⁇ antagonist activity Therefore, with regard to RAR ⁇ , this drug has an activity opposite to that of ATRA.
  • rat pups were subjected to identical daily injections until day 13.
  • a set of rat pups were sacrificed at day 4 and at day 21 by anesthesia with phenobarbitol sodium and scission of the abdominal aorta.
  • rat lungs were fixed and histological sections prepared essentially as described in Massaro et al., Am . J. Physiol . 270: L305 (1996), incorporated by reference herein. The histological sections were viewed and photographs taken under light microscopy.
  • the data also indicate that the increase in lung air volume seen in the first few days is an event independent from the presence or absence of RAR receptors or the presence or absence of an RAR modulating ligand, as shown in Figs. 2A-2D.
  • the septation stage of lung development can therefore be uncoupled from the increase in lung volume seen immediately post birth.
  • modulating of RAR receptors can be used to specifically affect septation without modulating other events in alveolar formation.
  • signal transduction through RAR receptors appears to be an endogenous modulator of alveolus formation.
  • agents having specific RAR modulating activity e.g., RAR ⁇ agonist activity
  • RAR ⁇ agonist activity e.g., RAR ⁇ agonist activity
  • treatment with a RAR ⁇ agonist plus all-trans retinoic acid may well augment the effect of either agent alone, allowing the use of lower doses of these drugs.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne des techniques et des compositions destinées au traitement des maladies pulmonaires telles que l'emphysème et/ou la dysplasie broncho-pulmonaire chez les mammifères. L'invention concerne également des techniques et des compositions favorisant la formation de septa alvéolaires et augmentant la surface d'échange gazeux d'un poumon de mammifère, destinées à la prévention et/ou au traitement de la destruction alvéolaire.
PCT/US2000/009494 1999-04-14 2000-04-11 Techniques et compositions pour le traitement et la prevention des maladies pulmonaires Ceased WO2000061182A2 (fr)

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Application Number Priority Date Filing Date Title
AU42224/00A AU4222400A (en) 1999-04-14 2000-04-11 Methods and compositions for the treatment and prevention of lung disease

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US12921499P 1999-04-14 1999-04-14
US60/129,214 1999-04-14

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6300350B1 (en) 1999-10-19 2001-10-09 Syntex (U.S.A.) Llc Treatment of emphysema using RARy selective retinoid agonists

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ZA882251B (en) * 1987-04-06 1989-11-29 Riker Laboratories Inc Substituted di-t-butylphenols
US5663357A (en) * 1995-11-22 1997-09-02 Allergan Substituted heteroarylamides having retinoid-like biological activity
US5675024A (en) * 1995-11-22 1997-10-07 Allergan Aryl or heteroaryl amides of tetrahydronaphthalene, chroman, thiochroman and 1,2,3,4,-tetrahydroquinoline carboxylic acids, having an electron withdrawing substituent in the aromatic or heteroaromatic moiety, having retinoid-like biological activity
US5739338A (en) * 1996-11-05 1998-04-14 Allergan N-aryl substituted tetrahydroquinolines having retinoid agonist, retinoid antagonist or retinoid inverse agonist type biological activity
US5919970A (en) * 1997-04-24 1999-07-06 Allergan Sales, Inc. Substituted diaryl or diheteroaryl methanes, ethers and amines having retinoid agonist, antagonist or inverse agonist type biological activity

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6300350B1 (en) 1999-10-19 2001-10-09 Syntex (U.S.A.) Llc Treatment of emphysema using RARy selective retinoid agonists

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AU4222400A (en) 2000-11-14

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