Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure

  • J Med Chem. 2020 Sep 10;63(17):9003-9019. doi: 10.1021/acs.jmedchem.9b02101.
Yoshikazu Asahina  1 ,  Nicholas R Wurtz  2 ,  Kazuto Arakawa  1 ,  Nancy Carson  2 ,  Kiyoshi Fujii  1 ,  Kazunori Fukuchi  1 ,  Ricardo Garcia  2 ,  Mei-Yin Hsu  2 ,  Junichi Ishiyama  1 ,  Bruce Ito  3 ,  Ellen Kick  2 ,  John Lupisella  2 ,  Shingo Matsushima  1 ,  Kohei Ohata  1 ,  Jacek Ostrowski  2 ,  Yoshifumi Saito  1 ,  Kosuke Tsuda  1 ,  Francisco Villarreal  3 ,  Hitomi Yamada  1 ,  Toshikazu Yamaoka  1 ,  Ruth Wexler  2 ,  David Gordon  2 ,  Yasushi Kohno  1
Affiliations
  • 1. Discovery Research Laboratories, Kyorin Pharmaceutical Co. Ltd., 2399-1, Nogi, Nogi-Machi, Shimotsuga-Gun, Tochigi 329-0114, Japan.
  • 2. Bristol-Myers Squibb Research and Development, P.O. Box 5400, Princeton, New Jersey 08534, United States.
  • 3. Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, California 92093, United States.
PMID: 32407089 DOI: 10.1021/acs.jmedchem.9b02101
Abstract

Formyl peptide receptor 2 (FPR2) agonists can stimulate resolution of inflammation and may have utility for treatment of diseases caused by chronic inflammation, including heart failure. We report the discovery of a potent and selective FPR2 agonist and its evaluation in a mouse heart failure model. A simple linear urea with moderate agonist activity served as the starting point for optimization. Introduction of a pyrrolidinone core accessed a rigid conformation that produced potent FPR2 and FPR1 agonists. Optimization of lactam substituents led to the discovery of the FPR2 selective agonist 13c, BMS-986235/LAR-1219. In cellular assays 13c inhibited neutrophil chemotaxis and stimulated macrophage phagocytosis, key end points to promote resolution of inflammation. Cardiac structure and functional improvements were observed in a mouse heart failure model following treatment with BMS-986235/LAR-1219.

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