2. Academic Validation
  3. Identification of a Hydroxypyrimidinone Compound ( 21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure

Identification of a Hydroxypyrimidinone Compound ( 21) as a Potent APJ Receptor Agonist for the Potential Treatment of Heart Failure

  • J Med Chem. 2021 Dec 23;64(24):18102-18113. doi: 10.1021/acs.jmedchem.1c01504.
Wei Meng 1,  Zulan Pi 1,  Robert Brigance 1,  Karen A Rossi 2,  William A Schumacher 3,  Jeffrey S Bostwick 3,  Peter S Gargalovic 3,  Joelle M Onorato 4,  Chiuwa E Luk 4,  Claudia N Generaux 4,  Tao Wang 5,  Ruth R Wexler 1,  Heather J Finlay 1
Affiliations

Affiliations

  • 1 Departments of Discovery Chemistry, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • 2 Computer-Assisted Drug Design, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • 3 Cardiovascular Drug Discovery Biology, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • 4 Pharmaceutical Candidate Optimization, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
  • 5 Leads Discovery and Optimization, Research and Development, Bristol Myers Squibb, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
PMID: 34855405 DOI: 10.1021/acs.jmedchem.1c01504
Abstract

This paper describes our continued efforts in the area of small-molecule apelin receptor agonists. Recently disclosed compound 2 showed an acceptable metabolic stability but demonstrated monodemethylation of the dimethoxyphenyl group to generate atropisomer metabolites in vitro. In this article, we extended the structure-activity relationship at the C2 position that led to the identification of potent pyrazole analogues with excellent metabolic stability. Due to the increased polarity at C2, the permeability for these compounds decreased. Further adjustment of the polarity by replacing the N1 2,6-dimethoxyphenyl group with a 2,6-diethylphenyl group and reoptimization for the potency of the C5 pyrroloamides resulted in potent compounds with improved permeability. Compound 21 displayed excellent pharmacokinetic profiles in rat, monkey, and dog models and robust pharmacodynamic efficacy in the rodent heart failure model. Compound 21 also showed an acceptable safety profile in preclinical toxicology studies and was selected as a backup development candidate for the program.

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