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Abstract

Abstract: DESCRIPTION (provided by applicant): The development of a platelet-rich thrombus on damaged endothelium or atherosclerotic plaques can severely impair the blood flow to vital organs, including the brain, heart, lungs, and kidneys. The contribution of platelets to the pathogenesis of potentially fatal ischemic and/or thromboembolic events, including stroke, myocardial infarct, and pulmonary embolism, is well documented. Therefore, the discovery of effective modulators of platelet function that can prevent thrombus formation is the focus of intensified efforts in translational hematology and cardiovascular biology research.The rationally designed small molecule chemical compound a-cyano-Beta-hydroxy-Beta-methyl-N-(2,5-dibromophenyl)-propenamide (LFM-A13) is a specific inhibitor of the TEC family protein tyrosine kinases, Bruton's tyrosine kinase (BTK) and TEC. Both BTK and TEC play an important role in platelet physiology by regulating the glycoprotein GPVI-FcRy-coupled collagen receptor signaling pathway. We have recently found that LFM-A13 inhibits (a) collagen-induced BTK/TEC stimulation, (b) BTK/TEC-dependent downstream signaling events, (c) biochemical and ultrastructural changes indicative of platelet activation, and (d) collagen-induced platelet aggregation. LFM-A13 was not toxic to mice when administered systemically at dose levels ranging from 1 mg/kg to 100 mg/kg. At nontoxic dose levels, LFM-A13 prolonged the tail bleeding times of mice and improved event-free survival in two mouse models of fatal pulmonary thromboembolism.An oral capsule formulation of LFM-A13 (LFM-A13-F) was developed and showed excellent bioavailability both in mice and dogs. We are now proposing to test the activity of this clinically applicable oral formulation in a mouse model of collagen-induced fatal thromboembolism. After establishing the single agent activity of LFM-A 13-F, we will also examine its antithrombotic effects in combination with the standard antiplatelet agents, dipyndamole or aspirin (alone or in combination). Also examined will be the effect of LFM-A13 alone or in combination with other drugs on the bleeding/clotting times in mice.

Thesaurus Terms:
cardiovascular disorder prevention, drug design /synthesis /production, platelet aggregation inhibitor, thromboembolism
biotherapeutic agent, blood, blood flow impedance, blood toxicology, collagen, dosage, drug discovery /isolation, drug screening /evaluation, hematology, pharmacokinetics, protein tyrosine kinase, vascular endothelium
laboratory mouse

Institution:	PARADIGM PHARMACEUTICALS, LLC
	2685 PATTON RD
	ST. PAUL, MN 55113
Fiscal Year:	2002
Department:
Project Start:	15-AUG-2002
Project End:	15-FEB-2003
ICD:	NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
IRG:	ZRG1