title: In vitro structure-activity relationship and in vivo characterization of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 antagonists.
abstract: The synthesis and structure-activity relationship of 1-(aryl)-3-(4-(amino)benzyl)urea transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of cyclic amine substituents are well tolerated at the 4-position of the benzyl group on compounds containing either an isoquinoline or indazole heterocyclic core. These compounds are potent antagonists of capsaicin activation of the TRPV1 receptor in vitro. Analogues, such as compound 45, have been identified that have good in vivo activity in animal models of pain. Further optimization of 45 resulted in compound 58 with substantially improved microsome stability and oral bioavailability, as well as in vivo activity.
authors.affiliation: Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. richard.j.perner@abbott.com
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Perner
authors.forename: Stanley
authors.initials: S
authors.lastname: DiDomenico
authors.forename: John R
authors.initials: JR
authors.lastname: Koenig
authors.forename: Arthur
authors.initials: A
authors.lastname: Gomtsyan
authors.forename: Erol K
authors.initials: EK
authors.lastname: Bayburt
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Guo Zhu
authors.initials: GZ
authors.lastname: Zheng
authors.forename: Sean C
authors.initials: SC
authors.lastname: Turner
authors.forename: Tammie
authors.initials: T
authors.lastname: Jinkerson
authors.forename: Brian S
authors.initials: BS
authors.lastname: Brown
authors.forename: Ryan G
authors.initials: RG
authors.lastname: Keddy
authors.forename: Kurill
authors.initials: K
authors.lastname: Lukin
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
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: Karen St
authors.initials: KS
authors.lastname: George
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
mesh_terms: D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004355:Drug Stability; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007546:Isoquinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000700:Analgesics; D007191:Indazoles; D007546:Isoquinolines; C523417:N-(3-trichloromethyl-4-(8-azabicyclo(3.2.1)octan-8-yl)benzyl)-N'-(indazol-4-yl)urea; D010671:Phenylurea Compounds; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493922:Trpv1 protein, rat; D014508:Urea