title: Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists.
abstract: Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC50 of 123nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States. Electronic address: blanco_maria@lilly.com.
authors.forename: Maria-Jesus
authors.initials: MJ
authors.lastname: Blanco
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Vetman
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Srinivasan
authors.initials: S
authors.lastname: Chandrasekhar
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Fisher
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Anita
authors.initials: A
authors.lastname: Harvey
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kuklish
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Mark
authors.initials: M
authors.lastname: Chambers
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Chaohua
authors.initials: C
authors.lastname: Lin
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Daniel
authors.initials: D
authors.lastname: Mudra
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Oskins
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Xu-Shan
authors.initials: XS
authors.lastname: Wang
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Xiao-Peng
authors.initials: XP
authors.lastname: Yu
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, United States.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Warshawsky
mesh_terms: D000818:Animals; D001565:Benzoates / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors*; D014961:X-Ray Diffraction
chemical_list: D001565:Benzoates; D058309:Receptors, Prostaglandin E, EP4 Subtype
keywords: Clinical candidate; EP4 antagonist; Inflammation; Pain; Prostaglandin E2 (PGE2)