Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1

Bioorg Med Chem Lett. 2017 Mar 15;27(6):1478-1483. doi: 10.1016/j.bmcl.2016.11.011. Epub 2016 Nov 7.

Abstract

We describe a novel class of acidic mPGES-1 inhibitors with nanomolar enzymatic and human whole blood (HWB) potency. Rational design in conjunction with structure-based design led initially to the identification of anthranilic acid 5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of 5 improved HWB potency by over 1000×, reduced CYP2C9 single point inhibition, and improved rat clearance, which led to the selection of [(cyclopentyl)ethyl]benzoic acid compound 16 for clinical studies. Compound 16 showed an IC80 of 24nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80 in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.

Keywords: Bioavailability; Biomarker; Prostaglandin pathway; mPGES-1.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Benzoates / chemistry*
  • Benzoates / pharmacology*
  • Crystallography, X-Ray
  • Dogs
  • Drug Discovery*
  • Microsomes / drug effects*
  • Microsomes / enzymology
  • Prostaglandin-E Synthases / antagonists & inhibitors*
  • Prostaglandin-E Synthases / chemistry
  • Rats

Substances

  • Benzoates
  • Prostaglandin-E Synthases