title: Chroman and tetrahydroquinoline ureas as potent TRPV1 antagonists.
abstract: Novel chroman and tetrahydroquinoline ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that aryl substituents on the 7- or 8-position of both bicyclic scaffolds imparted the best in vitro potency at TRPV1. The most potent chroman ureas were assessed in chronic and acute pain models, and compounds with the ability to cross the blood-brain barrier were shown to be highly efficacious. The tetrahydroquinoline ureas were found to be potent CYP3A4 inhibitors, but replacement of bulky substituents at the nitrogen atom of the tetrahydroisoquinoline moiety with small groups such as methyl can minimize the inhibition.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: Steven P
authors.initials: SP
authors.lastname: Latshaw
authors.forename: John R
authors.initials: JR
authors.lastname: Koenig
authors.forename: Jerome F
authors.initials: JF
authors.lastname: Daanen
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Bianchi
authors.forename: Chengmin
authors.initials: C
authors.lastname: Zhong
authors.forename: Shailen
authors.initials: S
authors.lastname: Joshi
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
mesh_terms: D002839:Chromans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011804:Quinolines / Q000737:chemistry; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D002839:Chromans; D011804:Quinolines; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea; C542964:1,2,3,4-tetrahydroquinoline