Design and optimization of benzimidazole-containing transient receptor potential melastatin 8 (TRPM8) antagonists.
Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel that is thermoresponsive to cool to cold temperatures (8-28 °C) and also may be activated by chemical agonists such as menthol and icilin. Antagonism of TRPM8 activation is currently under investigation for the treatment of painful conditions related to cold, such as cold allodynia and cold hyperalgesia. The design, synthesis, and optimization of a class of selective TRPM8 antagonists based on a benzimidazole scaffold is described, leading to the identification of compounds that exhibited potent antagonism of TRPM8 in cell-based functional assays for human, rat, and canine TRPM8 channels. Numerous compounds in the series demonstrated excellent in vivo activity in the TRPM8-selective "wet-dog shakes" (WDS) pharmacodynamic model and in the rat chronic constriction injury (CCI)-induced model of neuropathic pain. Taken together, the present results suggest that the in vivo antagonism of TRPM8 constitutes a viable new strategy for treating a variety of disorders associated with cold hypersensitivity, including certain types of neuropathic pain.
Janssen Research and Development, Spring House, Pennsylvania 19477-0776, United States.
Daniel J
DJ
Parks
William H
WH
Parsons
Raymond W
RW
Colburn
Sanath K
SK
Meegalla
Shelley K
SK
Ballentine
Carl R
CR
Illig
Ning
N
Qin
Yi
Y
Liu
Tasha L
TL
Hutchinson
Mary Lou
ML
Lubin
Dennis J
DJ
Stone
Judith F
JF
Baker
Craig R
CR
Schneider
Jianya
J
Ma
Bruce P
BP
Damiano
Christopher M
CM
Flores
Mark R
MR
Player
D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D003251:Constriction, Pathologic / Q000188:drug therapy / Q000503:physiopathology; D004285:Dogs; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy / Q000503:physiopathology; D066298:In Vitro Techniques; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008862:Microsomes, Liver / Q000378:metabolism; D009437:Neuralgia / Q000188:drug therapy / Q000503:physiopathology; D051381:Rats; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
C562242:3-(7-trifluoromethyl-5-(2-trifluoromethylphenyl)-1H-benzimidazol-2-yl)-1-oxa-2-azaspiro(4.5)dec-2-ene; D000700:Analgesics; D001562:Benzimidazoles; D007555:Isoxazoles; D050053:TRPM Cation Channels; C425966:TRPM8 protein, human; C498947:Trpm8 protein, rat