title: Naphthalene/quinoline amides and sulfonylureas as potent and selective antagonists of the EP4 receptor.
abstract: Two new series of EP(4) antagonists based on naphthalene/quinoline scaffolds have been identified as part of our on-going efforts to develop treatments for inflammatory pain. One series contains an acidic sulfonylurea pharmacophore, whereas the other is a neutral amide. Both series show subnanomolar intrinsic binding potency towards the EP(4) receptor, and excellent selectivity towards other prostanoid receptors. While the amide series generally displays poor pharmacokinetic parameters, the sulfonylureas exhibit greatly improved profile. MF-592, the optimal compound from the sulfonylurea series, has a desirable overall preclinical profile that suggests it is suitable for further development.
authors.affiliation: Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Ltd, 16711 Trans-Canada Hwy. Kirkland, Québec, Canada H9H 3L1.
authors.forename: Jason D
authors.initials: JD
authors.lastname: Burch
authors.forename: Julie
authors.initials: J
authors.lastname: Farand
authors.forename: John
authors.initials: J
authors.lastname: Colucci
authors.forename: Claudio
authors.initials: C
authors.lastname: Sturino
authors.forename: Yves
authors.initials: Y
authors.lastname: Ducharme
authors.forename: Richard W
authors.initials: RW
authors.lastname: Friesen
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Lévesque
authors.forename: Sébastien
authors.initials: S
authors.lastname: Gagné
authors.forename: Mark
authors.initials: M
authors.lastname: Wrona
authors.forename: Alex G
authors.initials: AG
authors.lastname: Therien
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Mathieu
authors.forename: Danielle
authors.initials: D
authors.lastname: Denis
authors.forename: Erika
authors.initials: E
authors.lastname: Vigneault
authors.forename: Daigen
authors.initials: D
authors.lastname: Xu
authors.forename: Patsy
authors.initials: P
authors.lastname: Clark
authors.forename: Steve
authors.initials: S
authors.lastname: Rowland
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Han
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D009281:Naphthalenes / Q000737:chemistry*; D011804:Quinolines / Q000737:chemistry*; D051381:Rats; D058309:Receptors, Prostaglandin E, EP4 Subtype / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D000577:Amides; D007211:Indoles; C557885:MF 592; D009281:Naphthalenes; D011804:Quinolines; D058309:Receptors, Prostaglandin E, EP4 Subtype; D013453:Sulfonylurea Compounds; C031721:naphthalene; C037219:quinoline