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.
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.
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States. Electronic address: jrech2@its.jnj.com.
Jason C
JC
Rech
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Anindya
A
Bhattacharya
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Bryan J
BJ
Branstetter
Janssen Pharmaceutical Research & Development L.L.C., Turnhoutseweg 30, Beerse, Belgium.
Christopher J
CJ
Love
Janssen Pharmaceutical Research & Development L.L.C., Turnhoutseweg 30, Beerse, Belgium.
Joseph E
JE
Leenaerts
Janssen Pharmaceutical Research & Development L.L.C., Turnhoutseweg 30, Beerse, Belgium.
Ludwig P
LP
Cooymans
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
William A
WA
Eckert
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Hong
H
Ao
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Qi
Q
Wang
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Sandra R
SR
Chaplan
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Alan D
AD
Wickenden
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
Alec D
AD
Lebsack
Janssen Pharmaceutical Research & Development L.L.C., 3210 Merryfield Row, San Diego, CA 92121, United States.
J Guy
JG
Breitenbucher
D000818:Animals; D055808:Drug Discovery; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D058920:Purinergic P2X Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D053583:Interleukin-1beta; D058920:Purinergic P2X Receptor Antagonists; D011804:Quinolines
IL-1β; Inflammation; P2X7; Pain