| Literature DB >> 32407089 |
Yoshikazu Asahina1, Nicholas R Wurtz2, Kazuto Arakawa1, Nancy Carson2, Kiyoshi Fujii1, Kazunori Fukuchi1, Ricardo Garcia2, Mei-Yin Hsu2, Junichi Ishiyama1, Bruce Ito3, Ellen Kick2, John Lupisella2, Shingo Matsushima1, Kohei Ohata1, Jacek Ostrowski2, Yoshifumi Saito1, Kosuke Tsuda1, Francisco Villarreal3, Hitomi Yamada1, Toshikazu Yamaoka1, Ruth Wexler2, David Gordon2, Yasushi Kohno1.
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.Entities:
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Year: 2020 PMID： 32407089 DOI： 10.1021/acs.jmedchem.9b02101
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446