title: Characterization of 3,3-dimethyl substituted N-aryl piperidines as potent microsomal prostaglandin E synthase-1 inhibitors.
abstract: Here we report on novel, potent 3,3-dimethyl substituted N-aryl piperidine inhibitors of microsomal prostaglandin E synthases-1(mPGES-1). Example 14 potently inhibited PGE2 synthesis in an ex vivo human whole blood (HWB) assay with an IC50 of 7nM. In addition, 14 had no activity in human COX-1 or COX-2 assays at 30μM, and failed to inhibit human mPGES-2 at 62.5μM in a microsomal prep assay. These data are consistent with selective mPGES-1-mediated reduction of PGE2. In dog, 14 had oral bioavailability (74%), clearance (3.62mL/(min*kg)) and volume of distribution (Vd,ss=1.6L/kg) values within our target ranges. For these reasons, 14 was selected for further study.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA. Electronic address: Kuklish_Steven@lilly.com.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kuklish
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.
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.
authors.forename: Adrian J
authors.initials: AJ
authors.lastname: Fretland
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
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.
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: 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: 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: Katherine M
authors.initials: KM
authors.lastname: Partridge
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: 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: D000072283:A549 Cells; D000818:Animals; D018360:Crystallography, X-Ray; D004285:Dogs; D006801:Humans; D010880:Piperidines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000071876:Prostaglandin-E Synthases / Q000037:antagonists & inhibitors*; D051381:Rats; D013045:Species Specificity; D013329:Structure-Activity Relationship
chemical_list: D010880:Piperidines; D000071876:Prostaglandin-E Synthases
keywords: Biomarker; Dog bioavailability; Prostaglandin pathway; mPGES-1