Myocardial infarction and stroke are caused by blood clots forming over atherosclerotic plaques (atherothrombosis). Production of PGE2 by atherosclerotic plaque exacerbates atherothrombosis and may limit the effectiveness of current therapeutics. As the deCODE chemistry team shows in this paper, if animals are treated with clopidogrel such that the platelets are covalently blocked, platelet aggregation can be restored by adding PGE2. The effect of PGE2 can be prevented by DG-041. Since clopidogrel affects global platelet function, in addition to preventing heart attacks it also increase bleeding. Since PGE2 is only produced by plaque but not by the arterial wall, DG-041 prevents clotting over plaques in animal studies, but does not increase bleeding.
In the article, the deCODE team describe the use of a ligand-based design strategy to develop peri-substituted bicylic acylsulfonamides as potent and selective EP3 antagonists. This has provided DG-041, a selective EP3 antagonist, with a unique therapeutic profile: DG-041 prevents the platelet aggregation response to PGE2, even when the platelets have been blocked by clopidogrel, but without affecting bleeding.
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deCODE chemistry, Inc. & deCODE biostructures, Inc. provide contract research services to pharmaceutical companies, biotechnology companies, academic institutions, and government facilities. deCODE chemistry & biostructures takes a collaborative approach to pharmaceutical research services through a seamless integration of chemistry and biology capabilities including protein production, multifaceted structural studies, lead identification, ex vivo and in vivo assays, cGMP manufacturing and regulatory capabilities which furnishes accelerated timelines for moving molecules from the concept and into the clinic. Visit deCODE chemistry & biostructures on the web at www.decodechembio.com.
