Discovery of 2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide as potent, selective and efficacious microsomal prostaglandin E2 synthase-1 (mPGES-1) inhibitor

Bioorg Med Chem Lett. 2016 Dec 15;26(24):5977-5984. doi: 10.1016/j.bmcl.2016.10.079. Epub 2016 Nov 1.

Abstract

The discovery and SAR of potent, selective dioxane-fused tricyclic benz[d]imidazole derivatives as mPGES-1 inhibitor are herein described. Various amide modifications in this series afforded many potent mPGES-1 inhibitors, of which 17d proved to be suitable for further profiling in vivo. Compound 17d {2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-[1,4]dioxino[2',3':3,4]benzo[1,2-d]imidazole-5-carboxamide} exhibited excellent mPGES-1 enzyme (IC50: 8nM), cell (A549 IC50: 16.24nM) and human whole blood potency (IC50: 249.9nM). In rodent species, 17d strongly inhibited guinea pig mPGES-1 (IC50: 10.79nM), but not the rat and mouse enzyme. Furthermore 17d displayed excellent in vitro selectivity over mPGES-2, cPGES, COX-enzymes (COX-1, 2), selectivity against other prostanoid synthases, favorable hERG and CEREP panel profile. Likewise, our lead 17d demonstrated good oral pharmacokinetic profiles and good CNS B/P ratio in rat and guinea pig. Lead 17d also unveiled good efficacy in LPS-induced thermal hyperalgesia pain model with ED50 of 36.7mg/kg, respectively.

Keywords: Benzimidazole; CSF concentration; PGE(2); Rheumatoid arthritis; Scaffold hopping; mPGES-1 inhibitor.

MeSH terms

  • Animals
  • Benzimidazoles / chemical synthesis
  • Benzimidazoles / chemistry
  • Benzimidazoles / pharmacology*
  • Dioxanes / chemical synthesis
  • Dioxanes / chemistry
  • Dioxanes / pharmacology*
  • Disease Models, Animal
  • Dogs
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Guinea Pigs
  • Hot Temperature
  • Humans
  • Hyperalgesia / drug therapy*
  • Lipopolysaccharides / antagonists & inhibitors
  • Lipopolysaccharides / pharmacology
  • Mice
  • Molecular Structure
  • Pain / drug therapy*
  • Prostaglandin-E Synthases / antagonists & inhibitors*
  • Prostaglandin-E Synthases / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

  • 2-((2-chloro-6-fluorophenyl)amino)-N-(3-fluoro-5-(trifluoromethyl)phenyl)-1-methyl-7,8-dihydro-1H-(1,4)dioxino(2',3'-3,4)benzo(1,2-d)imidazole-5-carboxamide
  • Benzimidazoles
  • Dioxanes
  • Enzyme Inhibitors
  • Lipopolysaccharides
  • Prostaglandin-E Synthases