Discovery of 2-(1H-indazol-1-yl)-thiazole derivatives as selective EP(1) receptor antagonists for treatment of overactive bladder by core structure replacement

Bioorg Med Chem Lett. 2014 Mar 1;24(5):1327-33. doi: 10.1016/j.bmcl.2014.01.052. Epub 2014 Jan 28.

Abstract

We have designed a series of potent EP1 receptor antagonists. These antagonists are a series of 2-(1H-indazol-1-yl)-thiazoles in which the core structure was replaced with pyrazole-phenyl groups. In preliminary conscious rat cystometry experiments, two representative candidates, 2 and 22, increased bladder capacity. In particular, the increase using 22 was approximately 2-fold that of the baseline. More detailed profiling of this compound and further optimization of this series promises to provide a novel class of drug for treating overactive bladder (OAB).

Keywords: Cystometry; EP(1) antagonist; Indazole; Overactive bladder; Thiazole.

MeSH terms

  • Animals
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Indazoles / chemistry*
  • Protein Binding
  • Rats
  • Receptors, Prostaglandin E, EP1 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP1 Subtype / metabolism
  • Structure-Activity Relationship
  • Thiazoles / chemistry*
  • Thiazoles / pharmacokinetics
  • Thiazoles / pharmacology
  • Thiazoles / therapeutic use
  • Urinary Bladder / drug effects
  • Urinary Bladder, Overactive / drug therapy

Substances

  • Indazoles
  • Receptors, Prostaglandin E, EP1 Subtype
  • Thiazoles