title: Discovery of novel aminothiadiazole amides as selective EP(3) receptor antagonists.
abstract: This Letter discloses a series of 2-aminothiadiazole amides as selective EP(3) receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP(3) receptor antagonists with excellent DMPK properties suitable for in vivo studies.
authors.affiliation: Department of Medicinal Chemistry, Metabolic Pathways Center of Excellence for Drug Discovery, GlaxoSmithKline Pharmaceuticals, 709 Swedeland Road, King of Prussia, PA 19406, United States. mark.a.hilfiker@gsk.com
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hilfiker
authors.forename: Ning
authors.initials: N
authors.lastname: Wang
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Hou
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Du
authors.forename: Mark A
authors.initials: MA
authors.lastname: Pullen
authors.forename: Melanie
authors.initials: M
authors.lastname: Nord
authors.forename: Rakesh
authors.initials: R
authors.lastname: Nagilla
authors.forename: Harvey E
authors.initials: HE
authors.lastname: Fries
authors.forename: Charlene W
authors.initials: CW
authors.lastname: Wu
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Sulpizio
authors.forename: Jon-Paul
authors.initials: JP
authors.lastname: Jaworski
authors.forename: Dwight
authors.initials: D
authors.lastname: Morrow
authors.forename: Richard M
authors.initials: RM
authors.lastname: Edwards
authors.forename: Jian
authors.initials: J
authors.lastname: Jin
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry*; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004285:Dogs; D015195:Drug Design; D006801:Humans; D008956:Models, Chemical; D015394:Molecular Structure; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: D000577:Amides; C545647:PTGER3 protein, human; C545649:Ptger3 protein, rat; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013830:Thiadiazoles