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.
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.
Gomtsyan
Arthur
A
Global Pharmaceutical Research and Development, Neuroscience Research, Abbott Laboratories, Abbott Park, IL 60064, USA. arthur.r.gomtsyan@abbott.com
Bayburt
Erol K
EK
Schmidt
Robert G
RG
Surowy
Carol S
CS
Honore
Prisca
P
Marsh
Kennan C
KC
Hannick
Steven M
SM
McDonald
Heath A
HA
Wetter
Jill M
JM
Sullivan
James P
JP
Jarvis
Michael F
MF
Faltynek
Connie R
CR
Lee
Chih-Hung
CH
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
C528492:ABT 102; D000700:Analgesics; D007191:Indazoles; D007192:Indenes; D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; D014508:Urea