Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1. Issue 6 (15th March 2017)

• Record Type: Journal Article
• Authors: Partridge, Katherine M.; Antonysamy, Stephen; Bhattachar, Shobha N.; Chandrasekhar, Srinivasan; Fisher, Matthew J.; Fretland, Adrian; Gooding, Karen; Harvey, Anita; Hughes, Norman E.; Kuklish, Steven L.; Luz, John G.; Manninen, Peter R.; McGee, James E.; Mudra, Daniel R.; Navarro, Antonio; Norman, Bryan H.; Quimby, Steven J.; Schiffler, Matthew A.; Sloan, Ashley V.; Warshawsky, Alan M.; Weller, Jennifer M.; York, Jeremy S.; Yu, Xiao-Peng
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 27:Issue 6(2017)
• Page Start: 1478
• Page End: 1483
• Publication Date: 2017-03-15
• Subjects: mPGES-1 -- Prostaglandin pathway -- Bioavailability -- Biomarker; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2016.11.011
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: 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 acid5, an mPGES-1 inhibitor with micromolar HWB potency. Structural modifications of5 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 compound16 for clinical studies. Compound16 showed an IC80 of 24 nM for inhibition of PGE2 formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of16 that exceeded its HWB IC80 in both rat (5 mg/kg) and dog (3 mg/kg) for over twelve hours.