WO2021211981A1 - Inhibiteurs de hsd17b13 sélectifs d'un substrat et utilisations de ceux-ci - Google Patents

Inhibiteurs de hsd17b13 sélectifs d'un substrat et utilisations de ceux-ci Download PDF

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Publication number
WO2021211981A1
WO2021211981A1 PCT/US2021/027703 US2021027703W WO2021211981A1 WO 2021211981 A1 WO2021211981 A1 WO 2021211981A1 US 2021027703 W US2021027703 W US 2021027703W WO 2021211981 A1 WO2021211981 A1 WO 2021211981A1
Authority
WO
WIPO (PCT)
Prior art keywords
hsd17b13
liver
inhibitor
subject
disease
Prior art date
Application number
PCT/US2021/027703
Other languages
English (en)
Inventor
Vincent FLORIO
Heather Kay Webb Hsu
Michael Carleton
Joshua Odingo
William Michael Gallatin
Original Assignee
Inipharm, Inc.
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 Inipharm, Inc. filed Critical Inipharm, Inc.
Publication of WO2021211981A1 publication Critical patent/WO2021211981A1/fr

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Classifications

    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics

Definitions

  • Disclosed herein is a method of treating a subject having a liver disease comprising administering to the subject in need thereof an estradiol oxidation-specific inhibitor of HSD17B13.
  • the estradiol oxidation-specific inhibitor of HSD17B13 provides a superior safety profile.
  • the estradiol oxidation-specific inhibitor of HSD17B13 reduces liver inflammation in the subject.
  • the estradiol oxidation-specific inhibition of HSD17B13 reduces fibrosis in the subject.
  • the liver disease is liver cirrhosis. In some embodiments, the liver disease is hepatic steatosis. In some embodiments, the liver disease is steatohepatitis.
  • HSD17B13 means hydroxysteroid 17-beta dehydrogenase 13 and refers to any nucleic acid of HSD17B13.
  • HSD17B13 includes a DNA sequence encoding HSD17B13, an RNA sequence transcribed from DNA encoding HSD17B13 (including genomic DNA comprising introns and exons). The target may be referred to in either upper or lower case.
  • Estradiol is a critical steroid mediator of processes throughout the body and is important for processes not only relating to sexual health, but also bone, skin and metabolic health. Maintenance of healthy levels of estradiol require a number of processes including estradiol oxidation by enzymes such as HSD17B13. Estradiol signaling is very sensitive to changes in estradiol levels. For this reason, it is important for the homeostasis of estradiol levels be maintained by both synthesis and degradation by enzymes such as HSD17B13. Changes in lipid mediators of inflammation and steroids body wide may be undesirable side effects of inhibiting leukotriene and estradiol metabolism.
  • retinol- oxidation specific inhibitors of HSD17B13 will thereby exhibit superior safety while treating and/or preventing liver inflammation and fibrosis.
  • the diastereomers have distinct physical properties (e.g., melting points, boiling points, solubilities, reactivity, etc.) and are separated by taking advantage of these dissimilarities.
  • the diastereomers are separated by chiral chromatography, or preferably, by separation/resolution techniques based upon differences in solubility.
  • the optically pure enantiomer is then recovered, along with the resolving agent, by any practical means that would not result in racemization.
  • Tritiated, i.e., 3 H and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavy isotopes such as deuterium, i.e ., 2 H, produces certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements.
  • Examples of pharmaceutically acceptable salts include those salts prepared by reaction of the compounds described herein with a mineral, organic acid or inorganic base, such salts including, acetate, acrylate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, bisulfite, bromide, butyrate, butyn-l,4-dioate, camphorate, camphorsulfonate, caproate, caprylate, chlorobenzoate, chloride, citrate, cyclopentanepropionate, decanoate, digluconate, dihydrogenphosphate, dinitrobenzoate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hexyne-1,6- dioate,
  • the liver disease, metabolic disease, or cardiovascular disease or disorder is metabolic syndrome, liver disease, fatty liver disease, chronic liver disease, liver cirrhosis, hepatic steatosis, steatohepatitis, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).
  • the liver disease, metabolic disease, or cardiovascular disease or disorder is NASH.
  • the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof is provided for use in reducing, improving, or regulating liver fibrosis in the individual. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, improving, or regulating triglyceride synthesis in the individual. In some embodiments, the compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, is provided for use in reducing, improving, or regulating lipid levels in the individual.
  • the liver disease, metabolic disease, or cardiovascular disease or disorder is metabolic syndrome, liver disease, fatty liver disease, chronic liver disease, liver cirrhosis, hepatic steatosis, steatohepatitis, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH).
  • the liver disease, metabolic disease, or cardiovascular disease or disorder is NASH.
  • compositions containing the compound(s) described herein are administered for prophylactic and/or therapeutic treatments.
  • the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest at least one of the symptoms of the disease or condition. Amounts effective for this use depend on the severity and course of the disease or condition, previous therapy, the patient’s health status, weight, and response to the drugs, and the judgment of the treating physician.
  • Therapeutically effective amounts are optionally determined by methods including, but not limited to, a dose escalation and/or dose ranging clinical trial.
  • any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which (i) the compound is administered once a day; or (ii) the compound is administered to the mammal multiple times over the span of one day.
  • Disclosed herein are method of treating a liver disease, metabolic disease, or cardiovascular disease using a compound disclosed herein, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, in combination with an additional therapeutic agent.

Abstract

La présente invention concerne en outre des inhibiteurs de HSD17B13 spécifiques à un substrat et des compositions pharmaceutiques comprenant lesdits inhibiteurs. Les composés et compositions de l'invention sont utiles pour le traitement d'une maladie du foie, d'une maladie métabolique ou d'une maladie cardiovasculaire, telle que la NAFLD ou la NASH.
PCT/US2021/027703 2020-04-18 2021-04-16 Inhibiteurs de hsd17b13 sélectifs d'un substrat et utilisations de ceux-ci WO2021211981A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202063012092P 2020-04-18 2020-04-18
US63/012,092 2020-04-18

Publications (1)

Publication Number Publication Date
WO2021211981A1 true WO2021211981A1 (fr) 2021-10-21

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2021/027703 WO2021211981A1 (fr) 2020-04-18 2021-04-16 Inhibiteurs de hsd17b13 sélectifs d'un substrat et utilisations de ceux-ci

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WO (1) WO2021211981A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022098757A1 (fr) * 2020-11-06 2022-05-12 Inipharm, Inc. Substrats et produits spécifiques de h17b13 en tant que marqueurs de maladie du foie et biomarqueurs pour le traitement de maladies du foie
WO2022098748A1 (fr) * 2020-11-06 2022-05-12 Inipharm, Inc. Utilisations d'inhibiteurs de hsd17b13

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110046147A1 (en) * 2007-08-25 2011-02-24 Universitat Des Saarlandes 17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of hormone-related diseases
WO2018190970A1 (fr) * 2017-04-11 2018-10-18 Regeneron Pharmaceuticals, Inc. Dosage de criblage de l'activité des modulateurs de membres de la famille des hydroxystéroïde (17-bêta) déshydrogénase (hsd17b)
WO2019075181A1 (fr) * 2017-10-11 2019-04-18 Regeneron Pharmaceuticals, Inc. Inhibition de hsd17b13 dans le traitement de la maladie hépatique chez des patients exprimant la variation pnpla3 i148m
WO2019183329A1 (fr) * 2018-03-21 2019-09-26 Ionis Pharmaceuticals, Inc. Modulation de l'expression de hsd17b13
WO2021003295A1 (fr) * 2019-07-02 2021-01-07 Regeneron Pharmaceuticals, Inc. Modulateurs de hsd17b13 et leurs procédés d'utilisation

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20110046147A1 (en) * 2007-08-25 2011-02-24 Universitat Des Saarlandes 17beta-hydroxysteroid dehydrogenase type 1 inhibitors for the treatment of hormone-related diseases
WO2018190970A1 (fr) * 2017-04-11 2018-10-18 Regeneron Pharmaceuticals, Inc. Dosage de criblage de l'activité des modulateurs de membres de la famille des hydroxystéroïde (17-bêta) déshydrogénase (hsd17b)
WO2019075181A1 (fr) * 2017-10-11 2019-04-18 Regeneron Pharmaceuticals, Inc. Inhibition de hsd17b13 dans le traitement de la maladie hépatique chez des patients exprimant la variation pnpla3 i148m
WO2019183329A1 (fr) * 2018-03-21 2019-09-26 Ionis Pharmaceuticals, Inc. Modulation de l'expression de hsd17b13
WO2021003295A1 (fr) * 2019-07-02 2021-01-07 Regeneron Pharmaceuticals, Inc. Modulateurs de hsd17b13 et leurs procédés d'utilisation

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022098757A1 (fr) * 2020-11-06 2022-05-12 Inipharm, Inc. Substrats et produits spécifiques de h17b13 en tant que marqueurs de maladie du foie et biomarqueurs pour le traitement de maladies du foie
WO2022098748A1 (fr) * 2020-11-06 2022-05-12 Inipharm, Inc. Utilisations d'inhibiteurs de hsd17b13

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