title: Heterocyclic 1,7-disubstituted indole sulfonamides are potent and selective human EP3 receptor antagonists.
abstract: We have developed a pharmacophore model for the EP(3) receptor antagonists based on its endogenous ligand PGE(2). This ligand-based design yielded a series of novel peri-substituted [4.3.0] bicyclic aromatics featuring 1-alklyaryl 7-heterocyclic sulfonamide substituents. The synthesized molecules are potent antagonists of human EP(3) receptor in vitro and show inhibition of rat platelets aggregation. Optimized derivatives display high selectivity over IP, FP, and other EP receptor panels.
authors.affiliation: Medicinal Chemistry Department, deCODE Chemistry, Inc, Woodridge, IL 60517, United States.
authors.forename: Georgeta
authors.initials: G
authors.lastname: Hategan
authors.forename: Alexandre M
authors.initials: AM
authors.lastname: Polozov
authors.forename: Wayne
authors.initials: W
authors.lastname: Zeller
authors.forename: Hua
authors.initials: H
authors.lastname: Cao
authors.forename: Rama K
authors.initials: RK
authors.lastname: Mishra
authors.forename: Alex S
authors.initials: AS
authors.lastname: Kiselyov
authors.forename: Jose
authors.initials: J
authors.lastname: Ramirez
authors.forename: Gudrún
authors.initials: G
authors.lastname: Halldorsdottir
authors.forename: Thornorkell
authors.initials: T
authors.lastname: Andrésson
authors.forename: Mark E
authors.initials: ME
authors.lastname: Gurney
authors.forename: Jasbir
authors.initials: J
authors.lastname: Singh
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006571:Heterocyclic Compounds; D007211:Indoles; C545647:PTGER3 protein, human; C545649:Ptger3 protein, rat; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013449:Sulfonamides