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Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-14 , 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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-05-14 , 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
Affiliation
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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.
中文翻译：
BMS-986235 / LAR-1219的发现：一种有效的甲酰肽受体2（FPR2）选择性激动剂，可预防心力衰竭。
甲酰基肽受体2（FPR2）激动剂可以刺激炎症消退，并且可以用于治疗由慢性炎症（包括心力衰竭）引起的疾病。我们报告了有效和选择性的FPR2激动剂的发现及其在小鼠心力衰竭模型中的评估。具有中等激动剂活性的简单线性尿素可作为优化的起点。引入吡咯烷酮核心获得了刚性构象，该构象产生了有效的FPR2和FPR1激动剂。内酰胺取代基的优化导致发现FPR2选择性激动剂13c BMS-986235 / LAR-1219。在细胞分析中13c抑制中性粒细胞趋化性并刺激巨噬细胞吞噬作用，这是促进炎症消退的关键终点。用BMS-986235 / LAR-1219处理后，在小鼠心力衰竭模型中观察到心脏结构和功能改善。
更新日期：2020-05-14
中文翻译：
BMS-986235 / LAR-1219的发现：一种有效的甲酰肽受体2（FPR2）选择性激动剂，可预防心力衰竭。
甲酰基肽受体2（FPR2）激动剂可以刺激炎症消退，并且可以用于治疗由慢性炎症（包括心力衰竭）引起的疾病。我们报告了有效和选择性的FPR2激动剂的发现及其在小鼠心力衰竭模型中的评估。具有中等激动剂活性的简单线性尿素可作为优化的起点。引入吡咯烷酮核心获得了刚性构象，该构象产生了有效的FPR2和FPR1激动剂。内酰胺取代基的优化导致发现FPR2选择性激动剂13c BMS-986235 / LAR-1219。在细胞分析中13c抑制中性粒细胞趋化性并刺激巨噬细胞吞噬作用，这是促进炎症消退的关键终点。用BMS-986235 / LAR-1219处理后，在小鼠心力衰竭模型中观察到心脏结构和功能改善。
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