ABSTRACT
A series of novel tetrahydropyridinecarboxamide TRPV1 antagonists were prepared and evaluated in an effort to optimize properties of previously described lead compounds from piperazinecarboxamide series. The compounds were evaluated for their ability to block capsaicin and acid-induced calcium influx in CHO cells expressing human TRPV1. The most potent of these TRPV1 antagonists were further characterized in pharmacokinetic, efficacy, and body temperature studies. On the basis of its pharmacokinetic, in vivo efficacy, safety, and toxicological properties, compound 37 was selected for further evaluation in human clinical trials.
Subject(s)
Aminopyridines/chemistry , Analgesics/chemistry , Pain/drug therapy , TRPV Cation Channels/antagonists & inhibitors , Aminopyridines/pharmacokinetics , Aminopyridines/pharmacology , Analgesics/pharmacokinetics , Analgesics/pharmacology , Animals , Body Temperature/drug effects , CHO Cells , Calcium/metabolism , Capsaicin/pharmacology , Cricetulus , Freund's Adjuvant , Ganglia, Spinal/cytology , Humans , Hydrogen-Ion Concentration , Male , Pain/etiology , Rats, Sprague-Dawley , Sensory Receptor Cells/drug effects , Sensory Receptor Cells/physiology , Stereoisomerism , Structure-Activity RelationshipABSTRACT
A series of N-substituted 3-(2-mercaptoethyl)-1H-indole-2-carboxylic acids were synthesized as inhibitors of glutamate carboxypeptidase II (GCPII). Those containing carboxybenzyl or carboxyphenyl groups at the N-position exhibited potent inhibitory activity against GCPII. These indole-based compounds represent the first example of achiral GCPII inhibitors and demonstrate greater tolerance of the GCPII active site for ligands with significant structural difference from the endogenous substrate, N-acetyl-aspartylglutamate.