Discovery of BMS-986235/LAR-1219: A Potent Formyl Peptide Receptor 2 (FPR2) Selective Agonist for the Prevention of Heart Failure
| Autor: | John A. Lupisella, Kiyoshi Fujii, David A. Gordon, Mei-Yin Hsu, Toshikazu Yamaoka, Yasuchi Kohno, Kohei Ohata, Kosuke Tsuda, Kazuto Arakawa, Nancy L. Carson, Kazunori Fukuchi, Ruth R. Wexler, Francisco Villarreal, Ellen K. Kick, Junichi Ishiyama, Jacek Ostrowski, Shingo Matsushima, Hitomi Yamada, Yoshifumi Saito, Bruce R. Ito, Yoshikazu Asahina, Ricardo Garcia, Nicholas R. Wurtz |
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| Rok vydání: | 2020 |
| Předmět: |
Agonist
medicine.drug_class Neutrophils Drug Evaluation Preclinical Inflammation Pharmacology 01 natural sciences Formyl peptide receptor 2 Macrophage phagocytosis 03 medical and health sciences chemistry.chemical_compound Mice Structure-Activity Relationship Phagocytosis Drug Discovery medicine Animals Humans Cardiac structure Receptors Lipoxin 030304 developmental biology Heart Failure 0303 health sciences Chemistry Chemotaxis Macrophages medicine.disease Receptors Formyl Peptide Pyrrolidinones 0104 chemical sciences Neutrophil chemotaxis 010404 medicinal & biomolecular chemistry Disease Models Animal HEK293 Cells Heart failure Lactam Microsomes Liver Molecular Medicine medicine.symptom |
| Zdroj: | Journal of medicinal chemistry. 63(17) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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