Structure-activity relationship studies leading to the identification of (2E)-3-[l-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-lH-indol-7-yl]-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041), a potent and selective prostanoid EP3 receptor antagonist, as a novel antiplatelet agent that does not prolong bleeding.
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.
Singh
Jasbir
J
deCODE Chemistry, Inc., 2501 Davey Road, Woodridge, Illinois 60517, USA. JSingh@decode.com
Zeller
Wayne
W
Zhou
Nian
N
Hategan
Georgeta
G
Mishra
Rama K
RK
Polozov
Alex
A
Yu
Peng
P
Onua
Emmanuel
E
Zhang
Jun
J
Ramírez
José L
JL
Sigthorsson
Gudmundur
G
Thorsteinnsdottir
Margret
M
Kiselyov
Alex S
AS
Zembower
David E
DE
Andrésson
Thorkell
T
Gurney
Mark E
ME
D000178:Acrylamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001777:Blood Coagulation / Q000187:drug effects; D055808:Drug Discovery; D006470:Hemorrhage; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D018078:Receptors, Prostaglandin E / Q000037:antagonists & inhibitors*; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
C531572:3-(1-((2,4-dichlorophenyl)methyl)-5-fluoro-3-methyl-1H-indol-7-yl)-N-((4,5-dichloro-2-thienyl)sulfonyl)-2-propenamide; D000178:Acrylamides; D008024:Ligands; C545647:PTGER3 protein, human; D010975:Platelet Aggregation Inhibitors; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D013450:Sulfones