title: Fused piperidines as a novel class of potent and orally available transient receptor potential melastatin type 8 (TRPM8) antagonists.
abstract: The transient receptor potential melastatin type 8 (TRPM8) is a nonselective cation channel primarily expressed in a subpopulation of sensory neurons that can be activated by a wide range of stimuli, including menthol, icilin, and cold temperatures (<25 °C). Antagonism of TRPM8 is currently under investigation as a new approach for the treatment of pain. As a result of our screening efforts, we identified tetrahydrothienopyridine 4 as an inhibitor of icilin-induced calcium influx in CHO cells expressing recombinant rat TRPM8. Exploration of the structure-activity relationships of 4 led to the identification of a potent and orally bioavailable TRPM8 antagonist, tetrahydroisoquinoline 87. Compound 87 demonstrated target coverage in vivo after oral administration in a rat pharmacodynamic model measuring the prevention of icilin-induced wet-dog shakes (WDS).
authors.affiliation: Department of Chemistry Research and Discovery, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799, United States. ntamayo@amgen.com
authors.forename: Nuria A
authors.initials: NA
authors.lastname: Tamayo
authors.forename: Yunxin
authors.initials: Y
authors.lastname: Bo
authors.forename: Vijay
authors.initials: V
authors.lastname: Gore
authors.forename: Vu
authors.initials: V
authors.lastname: Ma
authors.forename: Nobuko
authors.initials: N
authors.lastname: Nishimura
authors.forename: Phi
authors.initials: P
authors.lastname: Tang
authors.forename: Hong
authors.initials: H
authors.lastname: Deng
authors.forename: Lana
authors.initials: L
authors.lastname: Klionsky
authors.forename: Sonya G
authors.initials: SG
authors.lastname: Lehto
authors.forename: Weiya
authors.initials: W
authors.lastname: Wang
authors.forename: Brad
authors.initials: B
authors.lastname: Youngblood
authors.forename: Jiyun
authors.initials: J
authors.lastname: Chen
authors.forename: Tiffany L
authors.initials: TL
authors.lastname: Correll
authors.forename: Michael D
authors.initials: MD
authors.lastname: Bartberger
authors.forename: Narender R
authors.initials: NR
authors.lastname: Gavva
authors.forename: Mark H
authors.initials: MH
authors.lastname: Norman
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D066298:In Vitro Techniques; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011744:Pyrimidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors*
chemical_list: D000700:Analgesics; D010880:Piperidines; D011744:Pyrimidinones; D050053:TRPM Cation Channels; C498947:Trpm8 protein, rat; C490483:icilin; D002118:Calcium