The discovery of 4-{1-[({2,5-dimethyl-4-[4-(trifluoromethyl)benzyl]-3-thienyl}carbonyl)amino]cyclopropyl}benzoic acid (MK-2894), a potent and selective prostaglandin E2 subtype 4 receptor antagonist

J Med Chem. 2010 Mar 11;53(5):2227-38. doi: 10.1021/jm901771h.

Abstract

The discovery of highly potent and selective second generation EP(4) antagonist MK-2894 (34d) is discussed. This compound exhibits favorable pharmacokinetic profile in a number of preclinical species and potent anti-inflammatory activity in several animal models of pain/inflammation. It also shows favorable GI tolerability profile in rats when compared to traditional NSAID indomethacin.

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacokinetics
  • Animals
  • Benzoates / chemical synthesis*
  • Benzoates / chemistry
  • Benzoates / pharmacokinetics
  • Cyclopropanes / chemical synthesis*
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacokinetics
  • Half-Life
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Pain / drug therapy
  • Prostaglandin Antagonists / chemical synthesis*
  • Prostaglandin Antagonists / chemistry
  • Prostaglandin Antagonists / pharmacokinetics
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Prostaglandin E / antagonists & inhibitors
  • Receptors, Prostaglandin E / metabolism*
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacokinetics

Substances

  • Analgesics
  • Benzoates
  • Cyclopropanes
  • Prostaglandin Antagonists
  • Receptors, Prostaglandin E
  • Thiophenes