title: Discovery and characterization of [(cyclopentyl)ethyl]benzoic acid inhibitors of microsomal prostaglandin E synthase-1.
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 IC80of 24nM for inhibition of PGE2formation in vitro in LPS-stimulated HWB. A single oral dose resulted in plasma concentrations of 16 that exceeded its HWB IC80in both rat (5mg/kg) and dog (3mg/kg) for over twelve hours.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: Partridge_Katherine@lilly.com.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Partridge
authors.affiliation: Eli Lilly Biotechnology Center, San Diego, CA 92121, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Antonysamy
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Shobha N
authors.initials: SN
authors.lastname: Bhattachar
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA; Retired.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Chandrasekhar
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA; Present/Permanent address: Discovery Sciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA.
authors.forename: Adrian
authors.initials: A
authors.lastname: Fretland
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA; Retired.
authors.forename: Karen
authors.initials: K
authors.lastname: Gooding
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA; Retired.
authors.forename: Anita
authors.initials: A
authors.lastname: Harvey
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Hughes
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kuklish
authors.affiliation: Eli Lilly Biotechnology Center, San Diego, CA 92121, USA.
authors.forename: John G
authors.initials: JG
authors.lastname: Luz
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Peter R
authors.initials: PR
authors.lastname: Manninen
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: James E
authors.initials: JE
authors.lastname: McGee
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mudra
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Antonio
authors.initials: A
authors.lastname: Navarro
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Norman
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Quimby
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schiffler
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Ashley V
authors.initials: AV
authors.lastname: Sloan
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Warshawsky
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Weller
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: York
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Yu
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004285:Dogs; D055808:Drug Discovery; D008861:Microsomes / Q000187:drug effects* / Q000201:enzymology; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D051381:Rats
chemical_list: D001565:Benzoates; D000071876:Prostaglandin-E Synthases
keywords: Bioavailability; Biomarker; Prostaglandin pathway; mPGES-1