Identification of 6-Hydroxypyrimidin-4(1 H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists

  • ACS Med Chem Lett. 2021 Oct 22;12(11):1766-1772. doi: 10.1021/acsmedchemlett.1c00385.
Zulan Pi  1 ,  James A Johnson  1 ,  Wei Meng  1 ,  Monique Phillips  1 ,  William A Schumacher  1 ,  Jeffrey S Bostwick  1 ,  Peter S Gargalovic  1 ,  Joelle M Onorato  1 ,  Claudia N Generaux  1 ,  Tao Wang  1 ,  Yan He  1 ,  David A Gordon  1 ,  Ruth R Wexler  1 ,  Heather J Finlay  1
Affiliations
  • 1. Research and Development, Bristol Myers Squibb Company, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
PMID: 34795866 DOI: 10.1021/acsmedchemlett.1c00385
Abstract

The apelin receptor (APJ) is a significant regulator of cardiovascular function and is involved in heart failure and Other cardiovascular diseases. (Pyr1)apelin-13 is one of the endogenous agonists of the APJ receptor. Administration of (Pyr1)apelin-13 increases cardiac output in preclinical models and humans. Recently we disclosed clinical lead BMS-986224 (1), a C3 oxadiazole pyridinone APJ receptor agonist with robust pharmacodynamic effects similar to (Pyr1)apelin-13 in an acute rat pressure-volume loop model. Herein we describe the structure-activity relationship of the carboxamides as oxadiazole bioisosteres at C3 of the pyridinone core and C5 of the respective pyrimidinone core. This study led to the identification of structurally differentiated 6-hydroxypyrimidin-4(1H)-one-3-carboxamide 14a with pharmacodynamic effects comparable to those of compound 1.

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