Inhibitors of short-chain dehydrogenase activity for treating coronary disorders

A technology of inhibitors and chemotherapeutic agents, applied in the field of inhibitors of short-chain dehydrogenase activity for the treatment of coronary artery disease, can solve problems such as myocardial function degradation and myocardial cell death

Pending Publication Date: 2020-03-17
CASE WESTERN RESERVE UNIV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, over time, the left ventricular cavity dilates, systolic pump function deteriorates, cardiomyocytes undergo apoptotic cell death, and myocardial function progressively deteriorates

Method used

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  • Inhibitors of short-chain dehydrogenase activity for treating coronary disorders
  • Inhibitors of short-chain dehydrogenase activity for treating coronary disorders
  • Inhibitors of short-chain dehydrogenase activity for treating coronary disorders

Examples

Experimental program
Comparison scheme
Effect test

preparation example Construction

[0238] Depending on the type of substituents used in the preparation of the 15-PGDH inhibitors as well as the intermediates and the chosen method of preparation, the novel 15-PGDH inhibitors may be in any possible isomeric form, such as substantially pure geometric (cis or trans) isomers, optical isomers (enantiomers) and racemates.

[0239] In some embodiments, 15-PGDH inhibitors of formula (VIII) may include compounds of formula (IX):

[0240]

[0241] and pharmaceutically acceptable salts thereof.

[0242] Advantageously, a 15-PDGH inhibitor of formula (IX) was found to: i) inhibit recombinant 15-PGDH at a concentration of 1 nM; ii) inhibit 15-PGDH in a cell line at a concentration of 100 nM; iii) increase PGE 2 production; iv) is chemically stable in aqueous solutions over a wide pH range; v) is chemically stable when incubated with hepatocyte extracts; vi) is chemically stable when incubated with hepatocyte cell lines; vii) when When injected IP into mice, exhibited...

Embodiment

[0286] This example shows results from a study in which the 15-PGDH inhibitor (+) SW033291 prevented doxorubicin-induced cardiomyopathy in mice. Doxorubicin-induced cardiomyopathy limits the total dose of doxorubicin that can be administered to cancer patients. Prevention of this effect would directly reduce the risk of cardiomyopathy in cancer patients receiving doxorubicin-containing regimens, and would also mean that cancer patients would not have to undergo treatment when total doxorubicin doses reach current cardiotoxicity-based dose limits. Discontinue active doxorubicin-based therapy.

[0287] figure 1 The design of the study is schematically shown in which male C57b16J mice received a cumulative dose of 15 mgk of doxorubicin at 7 doses of 2.15 mpk per day on study days 1 to 7. The 15-PGDH inhibitor (+) SW033291 was administered by oral gavage at a dose of 25 mpk twice daily during days 1-14 of the study as a solution in a vehicle of 10% ethanol and 90% soybean oil. ...

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Abstract

A method of treating preventing, minimizing, and/or reversing congestive heart failure, cardiomyopathy, and/or reduction of cardiac ejection fraction in a subject in need thereof includes administering to the subject a therapeutically effective amount of a 15-PGDH inhibitor.

Description

[0001] related application [0002] This application claims priority to US Provisional Application No. 62 / 483,177, filed April 7, 2017, the subject matter of which is incorporated herein by reference in its entirety. [0003] Government funding [0004] This invention was made with government support under Grant Numbers P50CA150964 and 5F32DK107156 awarded by the National Institutes of Health. The US Government has certain rights in this invention. Background technique [0005] Congestive heart failure, one of the leading causes of death in industrialized countries, results from an increased workload on the heart and a progressive decline in its pumping capacity. Initially, increased workload due to hypertension or loss of contractile tissue induces compensatory cardiomyocyte hypertrophy and left ventricular wall thickening, which enhances contractility and preserves cardiac function. However, over time, the left ventricular cavity dilates, systolic pump function deteriorat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/4365A61K31/437A61K31/444A61K31/495A61K31/496A61K31/519
CPCA61K31/4365A61K31/497A61K31/501A61K31/506A61K31/704A61P9/00A61K2300/00A61K31/4355A61K31/437A61K31/496A61K31/519A61K31/5377A61K31/7048C07K16/32
Inventor S·马尔科维兹W·J·何Y·袁M·杰恩M·萨巴赫J·瑞迪N·威廉姆斯
Owner CASE WESTERN RESERVE UNIV
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