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

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

Affiliation

  • 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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