Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile

Bioorg Med Chem Lett. 2016 Feb 1;26(3):931-935. doi: 10.1016/j.bmcl.2015.12.057. Epub 2015 Dec 25.

Abstract

Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.

Keywords: EP4 receptor antagonist; Human whole blood (hWB) assay; Inflammation; Pain; Prostaglandin E2; Structure–activity relationship (SAR).

MeSH terms

  • Animals
  • Benzoic Acid / chemistry*
  • Benzoic Acid / pharmacokinetics
  • Benzoic Acid / therapeutic use
  • Disease Models, Animal
  • Dogs
  • Drug Evaluation, Preclinical
  • Half-Life
  • Humans
  • Inhibitory Concentration 50
  • Pain / drug therapy
  • Picolines / chemistry*
  • Protein Binding
  • Rats
  • Receptors, Prostaglandin E, EP4 Subtype / antagonists & inhibitors*
  • Receptors, Prostaglandin E, EP4 Subtype / metabolism
  • Structure-Activity Relationship

Substances

  • Picolines
  • Receptors, Prostaglandin E, EP4 Subtype
  • Benzoic Acid
  • 3-methylpyridine