jm9b02101_si_002.csv (4.86 kB)
Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure
dataset
posted on 2020-05-25, 04:47 authored by Yoshikazu Asahina, Nicholas R. Wurtz, Kazuto Arakawa, Nancy Carson, Kiyoshi Fujii, Kazunori Fukuchi, Ricardo Garcia, Mei-Yin Hsu, Junichi Ishiyama, Bruce Ito, Ellen Kick, John Lupisella, Shingo Matsushima, Kohei Ohata, Jacek Ostrowski, Yoshifumi Saito, Kosuke Tsuda, Francisco Villarreal, Hitomi Yamada, Toshikazu Yamaoka, Ruth Wexler, David Gordon, Yasushi KohnoFormyl 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.
