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ID: ALA3856256

Journal: Bioorg Med Chem Lett

Title: The discovery and preclinical characterization of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists.

Authors: Rech JC, Bhattacharya A, Branstetter BJ, Love CJ, Leenaerts JE, Cooymans LP, Eckert WA, Ao H, Wang Q, Chaplan SR, Wickenden AD, Lebsack AD, Breitenbucher JG.

Abstract: The synthesis, SAR and preclinical characterization of a series of 6-chloro-N-(2-(4,4-difluoropiperidin-1-yl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethyl)quinoline-5-carboxamide based P2X7 antagonists is described herein. The lead compounds are potent inhibitors in Ca(2+) flux and whole blood IL-1β P2X7 release assays at both human and mouse isoforms. Compound 1e showed a robust reduction of IL-1β release in a mouse ex vivo model with a 50mg/kg oral dose. Evaluation of compound 1e in the mouse SNI tactile allodynia, carrageenan-induced paw edema or CIA models resulted in no analgesic or anti-inflammatory effects.

CiteXplore: 27595421

DOI: 10.1016/j.bmcl.2016.08.029