title: Discovery and characterization of a potent and selective EP4 receptor antagonist.
abstract: EP4 is a prostaglandin E2 receptor that is a target for potential anti-nociceptive therapy. Described herein is a class of amphoteric EP4 antagonists which reverses PGE2-induced suppression of TNFα production in human whole blood. From this class, a potent and highly bioavailable compound (6) has been selected for potential clinical studies. EP4 binding and functional data, selectivity, and pharmacokinetic properties of this compound are included.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285 USA. Electronic address: schifflerma@lilly.com.
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: 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: 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: Steven L
authors.initials: SL
authors.lastname: Kuklish
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285 USA.
authors.forename: Xu-Shan
authors.initials: XS
authors.lastname: Wang
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: D000700:Analgesics / Q000737:chemistry* / Q000378:metabolism / Q000493:pharmacokinetics; D000818:Animals; D001773:Blood Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D006207:Half-Life; D006801:Humans; D008070:Lipopolysaccharides / Q000633:toxicity; D011485:Protein Binding; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000700:Analgesics; D008070:Lipopolysaccharides; D058309:Receptors, Prostaglandin E, EP4 Subtype; D014409:Tumor Necrosis Factor-alpha
keywords: Amphoteric; Dog bioavailability; EP(4) antagonist; Prostaglandin pathway