title: Novel transient receptor potential vanilloid 1 receptor antagonists for the treatment of pain: structure-activity relationships for ureas with quinoline, isoquinoline, quinazoline, phthalazine, quinoxaline, and cinnoline moieties.
abstract: Novel transient receptor potential vanilloid 1 (TRPV1) receptor antagonists with various bicyclic heteroaromatic pharmacophores were synthesized, and their in vitro activity in blocking capsaicin activation of TRPV1 was assessed. On the basis of the contribution of these pharmacophores to the in vitro potency, they were ranked in the order of 5-isoquinoline > 8-quinoline = 8-quinazoline > 8-isoquinoline > or = cinnoline approximately phthalazine approximately quinoxaline approximately 5-quinoline. The 5-isoquinoline-containing compound 14a (hTRPV1 IC50 = 4 nM) exhibited 46% oral bioavailability and in vivo activity in animal models of visceral and inflammatory pain. Pharmacokinetic and pharmacological properties of 14a are substantial improvements over the profile of the high-throughput screening hit 1 (hTRPV1 IC50 = 22 nM), which was not efficacious in animal pain models and was not orally bioavailable.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 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: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Guo Zhu
authors.initials: GZ
authors.lastname: Zheng
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: Sean
authors.initials: S
authors.lastname: Turner
authors.forename: Tammie
authors.initials: T
authors.lastname: Jinkerson
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hannick
authors.forename: Bryan S
authors.initials: BS
authors.lastname: Macri
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Carol T
authors.initials: CT
authors.lastname: Wismer
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Jill
authors.initials: J
authors.lastname: Wetter
authors.forename: Kent D
authors.initials: KD
authors.lastname: Stewart
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Oie
authors.forename: Michael F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Connie R
authors.initials: CR
authors.lastname: Faltynek
authors.forename: Chih-Hung
authors.initials: CH
authors.lastname: Lee
mesh_terms: D015746:Abdominal Pain / Q000188:drug therapy; D000284:Administration, Oral; D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001682:Biological Availability; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D010146:Pain / Q000188:drug therapy*; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011955:Receptors, Drug / Q000037:antagonists & inhibitors*; D055672:Static Electricity; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000700:Analgesics; D006574:Heterocyclic Compounds, 2-Ring; D007546:Isoquinolines; C497147:N-isoquinolin-5-yl-N'-(4-trifluoromethylbenzyl)urea; D011799:Quinazolines; D011804:Quinolines; D011955:Receptors, Drug; D014508:Urea; C476282:cinnoline; D002118:Calcium