title: Discovery and Characterization of 2-Acylaminoimidazole Microsomal Prostaglandin E Synthase-1 Inhibitors.
abstract: As part of a program aimed at the discovery of antinociceptive therapy for inflammatory conditions, a screening hit was found to inhibit microsomal prostaglandin E synthase-1 (mPGES-1) with an IC50 of 17.4 μM. Structural information was used to improve enzyme potency by over 1000-fold. Addition of an appropriate substituent alleviated time-dependent cytochrome P450 3A4 (CYP3A4) inhibition. Further structure-activity relationship (SAR) studies led to 8, which had desirable potency (IC50 = 12 nM in an ex vivo human whole blood (HWB) assay) and absorption, distribution, metabolism, and excretion (ADME) properties. Studies on the formulation of 8 identified 8·H3PO4 as suitable for clinical development. Omission of a lipophilic portion of the compound led to 26, a readily orally bioavailable inhibitor with potency in HWB comparable to celecoxib. Furthermore, 26 was selective for mPGES-1 inhibition versus other mechanisms in the prostanoid pathway. These factors led to the selection of 26 as a second clinical candidate.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schiffler
authors.affiliation: Eli Lilly Biotechnology Center , San Diego, California 92121, United States.
authors.forename: Stephen
authors.initials: S
authors.lastname: Antonysamy
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Shobha N
authors.initials: SN
authors.lastname: Bhattachar
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Kristina M
authors.initials: KM
authors.lastname: Campanale
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Chandrasekhar
authors.affiliation: Eli Lilly Biotechnology Center , San Diego, California 92121, United States.
authors.forename: Bradley
authors.initials: B
authors.lastname: Condon
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Prashant V
authors.initials: PV
authors.lastname: Desai
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
authors.affiliation: Eli Lilly Biotechnology Center , San Diego, California 92121, United States.
authors.forename: Christopher
authors.initials: C
authors.lastname: Groshong
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Anita
authors.initials: A
authors.lastname: Harvey
authors.affiliation: Eli Lilly Biotechnology Center , San Diego, California 92121, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Norman E
authors.initials: NE
authors.lastname: Hughes
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Jones
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Euibong J
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kuklish
authors.affiliation: Eli Lilly Biotechnology Center , San Diego, California 92121, United States.
authors.forename: John G
authors.initials: JG
authors.lastname: Luz
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Bryan H
authors.initials: BH
authors.lastname: Norman
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Windlesham, Surrey GU20 6PH, United Kingdom.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Rathmell
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: John R
authors.initials: JR
authors.lastname: Rizzo
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Thomas W
authors.initials: TW
authors.lastname: Seng
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Stefan J
authors.initials: SJ
authors.lastname: Thibodeaux
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Woods
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Jeremy S
authors.initials: JS
authors.lastname: York
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company , Indianapolis, Indiana 46285, United States.
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Yu
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001682:Biological Availability; D000068579:Celecoxib / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D004285:Dogs; D055808:Drug Discovery; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D019746:Intramolecular Oxidoreductases / Q000037:antagonists & inhibitors*; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology*; D008958:Models, Molecular; D000071876:Prostaglandin-E Synthases; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D007093:Imidazoles; D051544:Cytochrome P-450 CYP3A; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; D000068579:Celecoxib