Heterocyclic 1,7-disubstituted indole sulfonamides are potent and selective human EP3 receptor antagonists.
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.
Hategan
Georgeta
G
Medicinal Chemistry Department, deCODE Chemistry, Inc, Woodridge, IL 60517, United States.
Polozov
Alexandre M
AM
Zeller
Wayne
W
Cao
Hua
H
Mishra
Rama K
RK
Kiselyov
Alex S
AS
Ramirez
Jose
J
Halldorsdottir
Gudrún
G
Andrésson
Thornorkell
T
Gurney
Mark E
ME
Singh
Jasbir
J
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*
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