Anti-platelet Compounds that Inhibit Thrombosis by Selective G-protein Modulation (BIDMC 622)

Category:    Therapeutics - Drugs

KeyWords:  Vascular/Thrombosis;  

BIDMC ID:    622

Abstract:

A class of small, cell-permeant molecules capable of inhibiting ex vivo platelet function and in vivo thrombus formation are described. The lead molecules act rapidly and reversibly to block platelet function, distinguishing them from acetylsalicylic acid (aspirin) and clopidogrel (plavix). These compounds are selective G-protein coupled receptor (GPCR) modulators that interfere with transmission of signal following ligation of certain GPCRs on platelets such as protease-activated receptor-1 (PAR1) and the A2A-adrenergic receptor. They target palmitoylation events required for efficient GPCR signaling.

Inventor:   R. Flaumenhaft, M.D., Ph.D.

Commercial Opportunity:

Applications include acute myocardial infarction, angina, bypass surgery, transplantation related ischemia, cerebrovascular disease, placental insufficiency, prosthetic heart valves, atrial fibrillation, and anticoagulant agents during blood collection.

Competitive Advantages:

This novel family of compounds has the following advantages over existing anti-platelet agents: * Novel mechanism of action; * Platelet secretion is inhibited completely; * Lipophilic properties make them candidates for oral administration; * Short half-life allows use as short-acting anti-platelet agents where invasive procedures are required (e.g., bypass surgery for acute myocardial infarction); * Effects are reversible and rapid compared with currently available oral agents, a critical consideration in the acute treatment of myocardial infarction, stroke, and other syndromes involving arterial thrombosis

Related Publications:

Flaumenhaft, R and Sim DS.  The platelet as a model for chemical genetics.  Chem Biol.  2003; 10: 481-486.

Sim DS, Furie BC, Furie B, and Flaumenhaft R.  A Novel Family of Antiplatelet Compounds Reveals a Role for Protein Palmitoylation in Platelet Activation and Thrombus Formation In Vivo.  Blood 2003; 102 (suppl.): 207.
 
Sim DS, Peterson BR, Creaser SP, and Flaumenhaft R.  Protein palmitoylation participates in PAR1-
mediated platelet activation.  Blood. 2004; 104 (suppl.): 1560.

Sim DS, Merrill-Skoloff G, Furie BC, Furie B, and Flaumenhaft R.  Initial accumulation of platelets during arterial thrombus formation in vivo is inhibited by elevation of basal cAMP levels.  Blood. 2004; 103: 2127-2134.

State of Development:

Ex vivo data demonstrates complete inhibition of the dominant platelet responses in thrombus formation (platelet aggregation and release of thrombogenic substances).  Lead molecules inhibit thrombus progression in vivo with no apparent effects on heart rate or blood pressure in an established mouse model of thrombus formationinvolved in thrombus formation (platelet aggregation and  release of thrombogenic substances).  Lead molecule is capable of altering thrombus progression in vivo and has no apparent effects on heart rate or blood pressure in a specific mouse model.  The cellular target of these molecules is currently being characterized.

Related Technology URL:

http://bidmc.harvard.edu/default.asp?leaf_id=3782

Patent Status:

US applications pending and published online

TVO Contact Info:
     Catherine M Lenich
     Senior Associate TVO
     clenich@bidmc.harvard.edu
     Phone: 617-667-0568   Fax: 617-667-0646

     Beth Israel Deaconess Medical Center
     Technology Ventures Office  Room: BR-0200
     330 Brookline Avenue
     Boston, MA 02215