title: Discovery of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442): a temperature-neutral transient receptor potential vanilloid-1 (TRPV1) antagonist with analgesic efficacy.
abstract: The synthesis and characterization of a series of selective, orally bioavailable 1-(chroman-4-yl)urea TRPV1 antagonists is described. Whereas first-generation antagonists that inhibit all modes of TRPV1 activation can elicit hyperthermia, the compounds disclosed herein do not elevate core body temperature in preclinical models and only partially block acid activation of TRPV1. Advancing the SAR of this series led to the eventual identification of (R)-1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea (A-1165442, 52), an analogue that possesses excellent pharmacological selectivity, has a favorable pharmacokinetic profile, and demonstrates good efficacy against osteoarthritis pain in rodents.
authors.affiliation: Research & Development, AbbVie Inc. , 1 North Waukegan Road, North Chicago, Illinois 60064, United States.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Voight
authors.forename: Arthur R
authors.initials: AR
authors.lastname: Gomtsyan
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Perner
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: Stanley
authors.initials: S
authors.lastname: DiDomenico
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Puttfarcken
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Torben R
authors.initials: TR
authors.lastname: Neelands
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: Ping
authors.initials: P
authors.lastname: Han
authors.forename: Regina M
authors.initials: RM
authors.lastname: Reilly
authors.forename: Pamela H
authors.initials: PH
authors.lastname: Franklin
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
authors.forename: Richard A
authors.initials: RA
authors.lastname: Nelson
authors.forename: Zhi
authors.initials: Z
authors.lastname: Su
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: King
authors.forename: James S
authors.initials: JS
authors.lastname: Polakowski
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Baker
authors.forename: Donna M
authors.initials: DM
authors.lastname: Gauvin
authors.forename: LaGeisha R
authors.initials: LR
authors.lastname: Lewis
authors.forename: Joseph P
authors.initials: JP
authors.lastname: Mikusa
authors.forename: Shailen K
authors.initials: SK
authors.lastname: Joshi
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Philip R
authors.initials: PR
authors.lastname: Kym
authors.forename: Michael E
authors.initials: ME
authors.lastname: Kort
mesh_terms: D000700:Analgesics / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D019540:Area Under Curve; D001831:Body Temperature / Q000187:drug effects* / Q000502:physiology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D057809:HEK293 Cells; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D008657:Metabolic Clearance Rate; D008956:Models, Chemical; D015394:Molecular Structure; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: C000593226:1-(7-chloro-2,2-bis(fluoromethyl)chroman-4-yl)-3-(3-methylisoquinolin-5-yl)urea; D000700:Analgesics; D007546:Isoquinolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea