Novel Antithrombotic Diadenosine Tetraphosphate Analogs

DESCRIPTION: Undesired platelet activation can be result of many common pathologies or interventions. Arterial thrombosis and the acute ischemic events that follow, such as myocardial infarction and stroke, are among the leading causes of death, incapacitation, and rising health care costs in the developed world. Therefore antiplatelet drugs have significant market share and clinical importance, and advances in this area can have a significant social impact. In the previous phases of this project we developed a series of new bis-adenosine tetraphosphate (Ap4A) analogs, which inhibit platelet aggregation by a unique new mechanism, targeting both platelet ADP receptors, P2Y1 and P2Y12. Our studies have indicated that this simultaneous targeting might have asynergistic effect on platelet aggregation inhibition. Simultaneous targeting of two synergistic targets can also provide for an additional margin of safety against undesired off-site target side effects. In phase II we studied the specificity and selectivity of he class, and identified a candidate with efficacy in vivo for further development. This candidate (CD) inhibits ADP and collagen induced platelet aggregation in the low nanomolar range. Furthermore, it showed high antithrombotic activity in the well-established preclinical, canine model of recurrent thrombosis mimicking unstable angina ( Folts model ). In this model it completely abolished the cyclic flow variation (recurrent thrombosis) in injured and restricted coronary artery at an infusion doseof 1.8 g/kg/min. In a dose escalation study in rats the CD had a profound effect on platelet reactivity, and relatively small increase of the bleeding time only at the highest dose studied (100 times higher than the maximum efficacious dose). It also showed no effect on hemodynamic parameters at any dose. It did not act as agonist or antagonist of human P2Y2, P2Y4, P2Y6, or P2X1 receptors, and had good safety margin in the endothelium P2Y-dependent guinea pig aorta relaxation model. Moreover, the antiplatelet effect of the CD is reversible, has very fast onset and offset of its in vivo activity, and is quickly clered from the systemic circulation. We also demonstrated that the CD can be synthesized and purified in multi-gram scales. In view of the uniqueproperties of the class and the promising results obtained in phase II, we propose to continue the preclinical development of the CD, in order to obtain the package of data which would enable us to secure investor or partner funding for initiation of clinical testing after IND submission, or alternatively to license the CD to a maor pharmaceutical company for further clinical development. Despite the recent advances in development of new types of antithrombotics and because of the high mortality and recurrence rate and major bleeding events among acute coronary syndrome patients, there is a significant need for new antiplatelet agents that: a) can reduce ischemic events without causing excessive bleeding, b) have low interpatient variability of the effect,c) are fast acting, assuring immediat patient protection, d) have quick reversibility of the effect, so the treatment can start before fial diagnosis and intervention strategy are in place. The main antiplatelet drugs in clinical use today - aspirin and clopidogrel - target platelet COX-1 and P2Y12 platelet receptors, respectively. Limited response to both drugs, often referred to as resistance , occurs in significant numbers of patients and is associated with poor clinical outcomes. No drugs have yet been identified that inhibit both P2Y1 and P2Y12 receptors. No rapidly reversible (within 1-2 hours) injectable antiplatelet drugs are currently available for clinical use for patients who are in need of antiplatelet therapy, and may be at risk for bleeding complications, or may need surgical intervention. Therefore, we expect the further development of the CD to result in a new antithrombotic drug with superior safety and efficacy, and therapeutic properties that will satisfy important unmet clinical needs,and reduce the mortality rate among patients with acute coronary syndrome. PUBLIC HEALTH RELEVANCE PUBLIC HEALTH RELEVANCE: Platelets play critical roles in hemostasis, but their aggregation can cause thrombosis. Antiplatelet drugs such as clopidogrel (Plavix(R)) are slow to exert effects and cause irreversible inhibition of platelets. We have synthesized novel compounds that have a unique mechanism of action and fast onset/offset of action, and could be used effectively during acute events, such as stroke, and during surgery.