title: Discovery of potent aryl-substituted 3-[(3-methylpyridine-2-carbonyl) amino]-2,4-dimethyl-benzoic acid EP4 antagonists with improved pharmacokinetic profile.
abstract: Two new series of EP4 antagonists containing a 3-methylaryl-2-carbonyl core have been identified. One series has a 3-substituted-phenyl core, while the other one incorporates a 3-substituted pyridine. Both series led to compounds with potent activity in functional and human whole blood (hWB) assays. In the pyridine series, compound 7a was found to be a highly potent and selective EP4 antagonist, with suitable rat and dog pharmacokinetic profiles.
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: 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; D019817:Benzoic Acid / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D004195:Disease Models, Animal; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006207:Half-Life; D006801:Humans; D020128:Inhibitory Concentration 50; D010146:Pain / Q000188:drug therapy; D010847:Picolines / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010847:Picolines; D058309:Receptors, Prostaglandin E, EP4 Subtype; D019817:Benzoic Acid; C053603:3-methylpyridine
keywords: EP4 receptor antagonist; Human whole blood (hWB) assay; Inflammation; Pain; Prostaglandin E2; Structure–activity relationship (SAR)