title: Identification of (R)-1-(5-tert-butyl-2,3-dihydro-1H-inden-1-yl)-3-(1H-indazol-4-yl)urea (ABT-102) as a potent TRPV1 antagonist for pain management.
abstract: Vanilloid receptor TRPV1 is a cation channel that can be activated by a wide range of noxious stimuli, including capsaicin, acid, and heat. Blockade of TRPV1 activation by selective antagonists is under investigation by several pharmaceutical companies in an effort to identify novel agents for pain management. Here we report that replacement of substituted benzyl groups by an indan rigid moiety in a previously described N-indazole- N'-benzyl urea series led to a number of TRPV1 antagonists with significantly increased in vitro potency and enhanced drug-like properties. Extensive evaluation of pharmacological, pharmacokinetic, and toxicological properties of synthesized analogs resulted in identification of ( R)-7 ( ABT-102). Both the analgesic activity and drug-like properties of ( R)-7 support its advancement into clinical pain trials.
authors.affiliation: Global Pharmaceutical Research and Development, Neuroscience Research, Abbott Laboratories, 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: Robert G
authors.initials: RG
authors.lastname: Schmidt
authors.forename: Carol S
authors.initials: CS
authors.lastname: Surowy
authors.forename: Prisca
authors.initials: P
authors.lastname: Honore
authors.forename: Kennan C
authors.initials: KC
authors.lastname: Marsh
authors.forename: Steven M
authors.initials: SM
authors.lastname: Hannick
authors.forename: Heath A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Jill M
authors.initials: JM
authors.lastname: Wetter
authors.forename: James P
authors.initials: JP
authors.lastname: Sullivan
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; D000882:Haplorhini; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007192:Indenes / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008862:Microsomes, Liver / Q000378:metabolism; D010146:Pain / Q000188:drug therapy / Q000209:etiology; D051381:Rats; D013237:Stereoisomerism; 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: C528492:ABT 102; D000700:Analgesics; D007191:Indazoles; D007192:Indenes; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea