Main > A1. CORP. INDEX. In-Iz > Inspire Pharmaceuticals/P > 2005. 09.26.2005. Cardiology

In another MEDI session, James G. Douglass III, a principal investigator in medicinal chemistry at Inspire Pharmaceuticals, Durham, N.C., discussed INS50589, a potent and selective inhibitor of platelet aggregation that is being developed for use in acute treatment of cardiovascular diseases. The drug is "reversible," meaning that its activity dissipates quickly when administration is discontinued, permitting levels of platelet aggregation to return to normal. Platelet aggregation forms thrombi (blood-factor aggregates), which can cause strokes, heart attacks, and other problems.

In the body, adenosine 59-diphosphate (ADP) is one of the main regulators of platelet aggregation and consequent thrombus formation. This process begins when two G-protein-coupled receptors, P2Y1 and P2Y12, are activated simultaneously by ADP. The receptors are attractive targets for antithrombotic medications, because inhibiting the binding of ADP at either one reduces platelet aggregation. "We studied the structure-activity relationships of modified mono- and dinucleotides at P2Y12 and identified lipophilic modifications to the ribose and base moieties that imparted potent, selective, and reversible antagonist properties at this receptor," Douglass said. These studies led to the identification of INS50589 as a drug candidate, owing to its strong binding to and potent inhibition of the P2Y12 receptor.

In preclinical studies and in a recently completed Phase I trial, the compound was shown to be a potent and reversible inhibitor of platelet aggregation. Inspire plans to develop it as an agent that will inhibit platelet aggregation and activation during cardiopulmonary bypass procedures. The drug s reversibility would enable normal platelet function to be restored quickly after surgery, potentially reducing postoperative complications such as blood loss and minimizing the need for transfusions of blood or blood products.



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