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.
Subject(s)
Heterocyclic Compounds/pharmacology , Indoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Sulfonamides/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Heterocyclic Compounds/chemical synthesis , Heterocyclic Compounds/chemistry , Humans , Indoles/chemical synthesis , Indoles/chemistry , Models, Molecular , Molecular Structure , Receptors, Prostaglandin E, EP3 Subtype , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were found to be efficient ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors. An optimized molecule 7c featured a sound profile and potency in the functional rat and human platelet aggregation assays.
Subject(s)
Acrylamides/chemical synthesis , Acrylamides/metabolism , Indoles/chemical synthesis , Indoles/metabolism , Receptors, Prostaglandin E/antagonists & inhibitors , Acrylamides/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Dogs , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Drug Stability , Haplorhini , Humans , Indoles/pharmacology , Mice , Rats , Receptors, Prostaglandin E/metabolism , Receptors, Prostaglandin E, EP3 SubtypeABSTRACT
A series of peri-substituted [4.3.0] bicyclic non-aromatic heterocycles have been identified as potent and selective hEP(3) receptor antagonists. These molecules adopt a hair-pin conformation that overlaps with the endogenous ligand PGE(2) and fits into an internally generated EP(3) pharmacophore model. Optimized compounds show good metabolic stability and improved solubility over their corresponding bicyclic aromatic analogs.
Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Receptors, Prostaglandin E/antagonists & inhibitors , Alprostadil/analogs & derivatives , Alprostadil/metabolism , Animals , CHO Cells , Chemistry, Pharmaceutical/methods , Cricetinae , Cricetulus , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Magnetic Resonance Spectroscopy , Prostaglandins/chemistry , Receptors, Prostaglandin E/chemistry , Receptors, Prostaglandin E, EP3 Subtype , Sulfonamides/chemistryABSTRACT
A series of potent and selective EP(3) receptor antagonists are described. Utilizing a pharmacophore model developed for the EP(3) receptor, a series of 3,4-disubstituted indoles were shown to be high affinity ligands for this target. These compounds showed high selectivity over IP, FP and other EP receptors and are potent antagonists in functional assays.
