Abstract
The EP(3) receptor on the platelet mediates prostaglandin E(2) potentiation of thrombogenic coagonists including collagen and adenosine diphosphate (ADP). A pharmacophore driven approach led to the identification of diverse peri-substituted heterocycles as potent and selective EP(3) receptor antagonists. A simultaneous chemical optimization and druglike assessment of prioritized molecules converged on a lead compound 50 (DG-041) that displayed favorable in vitro and functional activities as an inhibitor of human platelet aggregation. This agent is currently in human clinical trials for the treatment of atherothrombosis.
MeSH terms
-
Acrylamides / chemical synthesis
-
Acrylamides / chemistry
-
Acrylamides / pharmacology*
-
Blood Coagulation / drug effects
-
Drug Discovery
-
Hemorrhage*
-
Humans
-
Ligands
-
Molecular Structure
-
Platelet Aggregation / drug effects*
-
Platelet Aggregation Inhibitors / chemical synthesis
-
Platelet Aggregation Inhibitors / chemistry
-
Platelet Aggregation Inhibitors / pharmacology*
-
Receptors, Prostaglandin E / antagonists & inhibitors*
-
Receptors, Prostaglandin E, EP3 Subtype
-
Stereoisomerism
-
Structure-Activity Relationship
-
Sulfones / chemical synthesis
-
Sulfones / chemistry
-
Sulfones / pharmacology*
Substances
-
3-(1-((2,4-dichlorophenyl)methyl)-5-fluoro-3-methyl-1H-indol-7-yl)-N-((4,5-dichloro-2-thienyl)sulfonyl)-2-propenamide
-
Acrylamides
-
Ligands
-
PTGER3 protein, human
-
Platelet Aggregation Inhibitors
-
Receptors, Prostaglandin E
-
Receptors, Prostaglandin E, EP3 Subtype
-
Sulfones