Identification of novel 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazoles: Lead generation and optimization toward potent and orally active EP1 receptor antagonists

Bioorg Med Chem. 2017 Jul 1;25(13):3406-3430. doi: 10.1016/j.bmc.2017.04.028. Epub 2017 Apr 26.

Abstract

Herein we described the design, synthesis and evaluation of a novel series of benzo[d]thiazole derivatives toward an orally active EP1 antagonist. Lead generation studies provided benzo[d]thiazole core from the four designed scaffolds. Optimization of this scaffold in terms of EP1 antagonist potency and ligand-lipophilicity efficiency (LLE; pIC50-clogP) led to a 1,2,3,6-tetrahydropyridyl-substituted benzo[d]thiazole derivative, 7r (IC50 1.1nM; LLE 4.7), which showed a good pharmacological effect when administered intraduodenally in a 17-phenyl trinor-PGE2 (17-PTP)-induced overactive bladder model in rats.

Keywords: Benzo[d]thiazole; EP(1) antagonist; Ligand-lipophilicity efficiency.

MeSH terms

  • Administration, Oral
  • Animals
  • Benzothiazoles / administration & dosage
  • Benzothiazoles / chemistry
  • Benzothiazoles / pharmacology*
  • Dinoprostone / analogs & derivatives
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Ligands
  • Molecular Structure
  • Rats
  • Receptors, Prostaglandin E, EP1 Subtype / antagonists & inhibitors*
  • Structure-Activity Relationship
  • Urinary Bladder, Overactive / chemically induced
  • Urinary Bladder, Overactive / drug therapy*

Substances

  • 17-phenyltrinorprostaglandin E2
  • Benzothiazoles
  • Ligands
  • Receptors, Prostaglandin E, EP1 Subtype
  • Dinoprostone