Alpha-methylation at benzylic fragment of N-aryl-N'-benzyl ureas provides TRPV1 antagonists with better pharmacokinetic properties and higher efficacy in inflammatory pain model.
SAR studies for N-aryl-N'-benzyl urea class of TRPV1 antagonists have been extended to cover alpha-benzyl alkylation. Alkylated compounds showed weaker in vitro potencies in blocking capsaicin activation of TRPV1 receptor, but possessed improved pharmacokinetic properties. Further structural manipulations that included replacement of isoquinoline core with indazole and isolation of single enantiomer led to TRPV1 antagonists like (R)-16a with superior pharmacokinetic properties and greater potency in animal model of inflammatory pain.
Gomtsyan
Arthur
A
Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. arthur.r.gomtsyan@abbott.com
Bayburt
Erol K
EK
Keddy
Ryan
R
Turner
Sean C
SC
Jinkerson
Tammie K
TK
Didomenico
Stanley
S
Perner
Richard J
RJ
Koenig
John R
JR
Drizin
Irene
I
McDonald
Heath A
HA
Surowy
Carol S
CS
Honore
Prisca
P
Mikusa
Joe
J
Marsh
Kennan C
KC
Wetter
Jill M
JM
Faltynek
Connie R
CR
Lee
Chih-Hung
CH
D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D007249:Inflammation / Q000188:drug therapy*; D008745:Methylation; D008954:Models, Biological; D010146:Pain / Q000188:drug therapy*; D051381:Rats; D050916:TRPV Cation Channels / Q000037:antagonists & inhibitors*; D014508:Urea / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use
D000700:Analgesics; D050916:TRPV Cation Channels; C493922:Trpv1 protein, rat; D014508:Urea