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.

Autor: Rech JC; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: jrech2@its.jnj.com., Bhattacharya A; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Branstetter BJ; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Love CJ; Janssen Pharmaceutical Research & Development L.L.C., Turnhoutseweg 30, Beerse, Belgium., Leenaerts JE; Janssen Pharmaceutical Research & Development L.L.C., Turnhoutseweg 30, Beerse, Belgium., Cooymans LP; Janssen Pharmaceutical Research & Development L.L.C., Turnhoutseweg 30, Beerse, Belgium., Eckert WA 3rd; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Ao H; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Wang Q; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Chaplan SR; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Wickenden AD; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Lebsack AD; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States., Breitenbucher JG; Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2016 Oct 01; Vol. 26 (19), pp. 4781-4784. Date of Electronic Publication: 2016 Aug 20.
DOI: 10.1016/j.bmcl.2016.08.029
Abstrakt: 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.
(Copyright © 2016 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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