Bioorganic and Medicinal Chemistry Letters p. 4781 - 4784 (2016)
Update date:2022-08-16
Topics:
Rech, Jason C.
Bhattacharya, Anindya
Branstetter, Bryan J.
Love, Christopher J.
Leenaerts, Joseph E.
Cooymans, Ludwig P.
Eckert, William A.
Ao, Hong
Wang, Qi
Chaplan, Sandra R.
Wickenden, Alan D.
Lebsack, Alec D.
Breitenbucher, J. Guy
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 Ca2+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 50?mg/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.
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