Discovery and optimization of pyridyl-cycloalkyl-carboxylic acids as inhibitors of microsomal prostaglandin E synthase-1 for the treatment of endometriosis

Bioorg Med Chem Lett. 2019 Sep 15;29(18):2700-2705. doi: 10.1016/j.bmcl.2019.07.007. Epub 2019 Jul 24.

Abstract

Here we report on novel and potent pyridyl-cycloalkyl-carboxylic acid inhibitors of microsomal prostaglandin E synthase-1 (PTGES). PTGES produces, as part of the prostaglandin pathway, prostaglandin E2 which is a well-known driver for pain and inflammation. This fact together with the observed upregulation of PTGES during inflammation suggests that blockade of the enzyme might provide a beneficial treatment option for inflammation related conditions such as endometriosis. Compound 5a, a close analogue of the screening hit, potently inhibited PTGES in vitro, displayed excellent PK properties in vitro and in vivo and demonstrated efficacy in a CFA-induced pain model in mice and in a rat dyspareunia endometriosis model and was therefore selected for further studies.

Keywords: PGE(2); PTGES; Pain; Prostaglandin pathway; mPGES-1.

MeSH terms

  • Animals
  • Carboxylic Acids / chemical synthesis
  • Carboxylic Acids / chemistry
  • Carboxylic Acids / pharmacology*
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Endometriosis / drug therapy*
  • Endometriosis / metabolism
  • Enzyme Inhibitors / chemical synthesis
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Inflammation / drug therapy
  • Inflammation / metabolism
  • Mice
  • Molecular Docking Simulation
  • Molecular Structure
  • Pain / drug therapy
  • Pain / metabolism
  • Prostaglandin-E Synthases / antagonists & inhibitors*
  • Prostaglandin-E Synthases / metabolism
  • Rats
  • Structure-Activity Relationship

Substances

  • Carboxylic Acids
  • Enzyme Inhibitors
  • Prostaglandin-E Synthases