title: Alpha-methylation at benzylic fragment of N-aryl-N'-benzyl ureas provides TRPV1 antagonists with better pharmacokinetic properties and higher efficacy in inflammatory pain model.
abstract: SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. arthur.r.gomtsyan@abbott.com
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: Ryan
authors.initials: R
authors.lastname: Keddy
authors.forename: Sean C
authors.initials: SC
authors.lastname: Turner
authors.forename: Tammie K
authors.initials: TK
authors.lastname: Jinkerson
authors.forename: Stanley
authors.initials: S
authors.lastname: Didomenico
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Perner
authors.forename: John R
authors.initials: JR
authors.lastname: Koenig
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Joe
authors.initials: J
authors.lastname: Mikusa
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D007249:Inflammation / Q000188:drug therapy*; D008745:Methylation; D008954:Models, Biological; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014508:Urea / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000700:Analgesics; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014508:Urea