The role of platelets in arterial thrombosis and cardiovascular disease has been well documented, and thus platelets have represented a major target of therapeutic intervention over the last decade. The present application (FastTrack Phase l/ll combination) is designed to develop a novel antagonist of P2Y12 (the ADP receptor on platelets and a validated drug target) that will overcome the limitations of clopidogrel, an approved irreversible, P2Y12 inhibitor that requires hepatic metabolism to generate the active intermediate. We have identified a direct-acting, reversible antagonist of P2Y12 called CT57537 that has high potency for this receptor and favorable pharmacokinetic properties (suitable half-life, low clearance, good oral bioavailability in multiple species). In this Phase I application, we will (1) determine whether CT57537 is antithrombotic in human and rodent ex vivo and in vivo models of thrombosis. To accomplish this, we will determine potency of CT57537 using (a) human and (b) mouse whole blood perfused through a collagen coated capillary under arterial shear and (c) in a mouse in vivo mesenteric artery FeCIS-induced injury model. Secondly, we will compare the antithrombotic/antihemostatic ratio for CT57537 to that of clopidogrel in a rat thrombosis model, and correlate in vivo antithrombotic efficacy with inhibition of ex vivo platelet aggregation at multiple drug doses. Successful completion of Phase I will allow us to proceed to Phase II studies where we will evaluate this compound in a canine model of thrombosis, evaluate the role of P2Y12 in platelet-mediated inflammatory events (plaque progression and neointimal proliferation), and complete the necessary toxicological studies with CT57537 necessary for filing an IND.
