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NOVEL ANTI-THROMBOTIC APPROACH FOR TREATMENT OF MYOCARDIAL INFARCTION

Award Number: R43HL090132
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/10/2007
PERIOD OF PERFORMANCE END DATE: 08/31/2008

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NOVEL ANTI-THROMBOTIC APPROACH FOR TREATMENT OF MYOCARDIAL INFARCTION - DESCRIPTION (provided by applicant): More than 850,000 myocardial infarctions (MI) occur in the US annually, 300,000 of which are recurrences, carrying with them a two-fold increased risk of death. Recurrent MI take place owing to the high rates of reocclusion of cardiac arteries observed following initially successful fibrinolytic therapy with t-PA or streptokinase. Plasmin-induced activation of the intrinsic coagulation system, proceeding via two tightly- linked enzymes, factor XII (FXII) and plasma kallikrein (PK), may be the mechanism for generation of new thrombin during fibrinolysis. Mice deficient in FXII are highly resistant to the formation of occluding arterial thrombi in multiple models of injury-mediated arterial thrombus formation. The extent of PK activation regulates the amount of FXII activity, and thus inhibition of PK would provide a novel anti-thrombotic therapeutic approach for the treatment of acute MI, especially as adjunctive therapy to current standard-of- care fibrinolytic treatments. We have generated novel small molecule PK inhibitors displaying both high potency for PK inhibition and selectivity against other enzymes in the intrinsic pathways. In addition, sensitive plasma-based assays have been developed to quantitatively measure the extent of inhibition of the intrinsic coagulation pathway resulting from PK inhibition. Using these assays, we have demonstrated that inhibition of PK is more effective than depletion of FXII for inhibiting thrombin generation and coagulation by the intrinsic pathway. We propose in Phase I to develop PK inhibitors that have defined potency, selectivity and pharmacokinetic properties, then test the best compounds in a mouse model of arterial thrombosis, so as to provide proof-of-concept that selective inhibition of PK could provide a novel therapeutic approach for reducing risk of reocclusion and reinfarction following fibrinolytic therapy for MI. The successful completion of Phase I will also result in the identification of one or more lead compounds suitable for preclinical development in Phase II for adjunctive therapy for MI patients undergoing fibrinolytic therapy. This project proposes that inhibition of the intrinsic coagulation pathway, to be accomplished by inhibition of a key enzyme of this pathway, plasma kallikrein (PK), would have significant therapeutic impact in reducing the risk of reocclusion and reinfarction in patients with mycorcardial infarction (MI) who have undergone fibrinolytic treatment. It seeks to optimize prototype novel small molecule inhibitors of PK to obtain lead molecules that will be tested in animal models of thrombosis in Phase I, then proceed into preclinical development in Phase II for adjunctive therapy for MI patients receiving fibrinolytic therapy.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2007 ( Subtotal = $224,868 )
2007	2007	ACTIVESITE PHARMACEUTICALS INC	626 BANCROFT WAY	BERKELEY	CA	94710	ALAMEDA	USA	Blood Diseases and Resources Research	000	1	9/8/2007	NEW	$224,868
														Subtotal = $224,868

Grand Total All Awards = $224,868

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NOVEL ANTI-THROMBOTIC APPROACH FOR TREATMENT OF MYOCARDIAL INFARCTION

Award Number: R43HL090132

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/10/2007

PERIOD OF PERFORMANCE END DATE: 08/31/2008

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