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

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

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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