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 EP3 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 EP3 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,Zeller, Wayne,Zhou, Nian,Hategan, Georgeta,Mishra, Rama K.,Polozov, Alex,Yu, Peng,Onua, Emmanuel,Zhang, Jun,Ramírez, José L.,Sigthorsson, Gudmundur,Thorsteinnsdottir, Margret,Kiselyov, Alex S.,Zembower, David E.,Andrésson, Thorkell,Gurney, Mark E.
scheme or table
p. 18 - 36
(2010/04/26)
PROCESS FOR PREPARING 7-(ACRYLOYL)INDOLES
The present invention involves a process for preparing substituted indoles, such as DTSI involving two sequential cross-coupling reactions.
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Page/Page column 12
(2008/06/13)
Development of a scalable process for DG-041, a potent EP3 receptor antagonist, via tandem heck reactions
DG-041 is a small molecule antagonist of the EP3 receptor for prostaglandin E2 that is in clinical development for treatment of peripheral artery disease (PAD). Originally produced using a six-step synthetic procedure, process optimization led to development of a four-step sequence that is readily scalable. The key step in the optimized sequence contains two sequential Heck reactions, involving an intramolecular Heck cyclization followed by an intermolecular Heck coupling, performed in one pot to produce a highly substituted indole core.
Zegar, Siead,Tokar, Christopher,Enache, Livia A.,Rajagopol, Venkat,Zeller, Wayne,O'Connell, Matthew,Singh, Jasbir,Muellner, Frank W.,Zembower, David E.
p. 747 - 753
(2012/12/29)
7-(ACRYLOYL) INDOLE COMPOSITIONS AND METHODS FOR MAKING AND USING SAME
The present invention is directed to pharmaceutical compositions of 7-(acryloyl) indoles, such as 4,5-Dichloro-thiophene-2-sulfonic acid [(E)-3-[1-(2,4-dichlorophenylmethyl)-5-fluoro-3-methyl-1H-indol-7-yl]-acryloyl]amide (DTSI). The invention is also dir
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(2010/11/29)
Sulfonamide peri-substituted bicyclics for occlusive artery disease
Acyl sulfonamide, peri-substituted, fused bicyclic ring compounds useful for the treatment or prophylaxis of a prostaglandin-mediated disease or condition are disclosed. The compounds are of the general formula A representative example is:
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(2008/06/13)
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