title: Structure-activity studies of a novel series of 5,6-fused heteroaromatic ureas as TRPV1 antagonists.
abstract: Novel 5,6-fused heteroaromatic ureas were synthesized and evaluated for their activity as TRPV1 antagonists. It was found that 4-aminoindoles and indazoles are the preferential cores for the attachment of ureas. Bulky electron-withdrawing groups in the para-position of the aromatic ring of the urea substituents imparted the best in vitro potency at TRPV1. The most potent derivatives were assessed in in vivo inflammatory and neuropathic pain models. Compound 46, containing the indazole core and a 3,4-dichlorophenyl group appended to it via a urea linker, demonstrated in vivo analgesic activity upon oral administration. This derivative also showed selectivity versus other receptors in the CEREP screen and exhibited acceptable cardiovascular safety at levels exceeding the therapeutic dose.
authors.affiliation: Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Il 60064, USA. irene.drizin@abbott.com
authors.forename: Irene
authors.initials: I
authors.lastname: Drizin
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 C
authors.initials: SC
authors.lastname: Turner
authors.forename: Tammie K
authors.initials: TK
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: 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 M
authors.initials: JM
authors.lastname: Wetter
authors.forename: James S
authors.initials: JS
authors.lastname: Polakowski
authors.forename: Jason A
authors.initials: JA
authors.lastname: Segreti
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: D000818:Animals; D066298:In Vitro Techniques; D007700:Kinetics; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D014508:Urea