86941-02-8Relevant articles and documents
Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure
Asahina, Yoshikazu,Wurtz, Nicholas R.,Arakawa, Kazuto,Carson, Nancy,Fujii, Kiyoshi,Fukuchi, Kazunori,Garcia, Ricardo,Hsu, Mei-Yin,Ishiyama, Junichi,Ito, Bruce,Kick, Ellen,Lupisella, John,Matsushima, Shingo,Ohata, Kohei,Ostrowski, Jacek,Saito, Yoshifumi,Tsuda, Kosuke,Villarreal, Francisco,Yamada, Hitomi,Yamaoka, Toshikazu,Wexler, Ruth,Gordon, David,Kohno, Yasushi
, p. 9003 - 9019 (2020)
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.
