Neelakantan Balasubramanian

Effect of a novel thrombin active-site inhibitor on arterial and venous thrombosis

The effects of a thrombin active-site inhibitor on arterial and venous thrombosis, and thrombin-induced thrombocytopenia were determined in anesthetized rats. Desamino D-Phe-Pro-Arg-aldehyde (BMY 44621) was administered before experimental intervention as a loading i.v. dose plus continuous i.v. infusion. Carotid artery thrombosis was produced by transmural vessel injury and vena cava thrombosis was produced by partial stasis of blood flow combined with endothelial injury. Thrombocytopenia was induced by an i.v. injection of human alpha-thrombin. BMY 44621 inhibited arterial and venous thrombosis in a dose-dependent manner. Its threshold antithrombotic dose for venous thrombosis was half of that for arterial thrombosis. Maximum reductions in thrombus weight were greater for venous (> 90%) compared to arterial (57%) thrombosis and correlated with 2-and 9-fold prolongation of ex vivo thrombin clotting time, respectively. A 40% reduction in platelet counts induced by thrombin injection was abolished by the threshold dose of BMY 44621 for inhibiting venous thrombosis. These experiments demonstrate that thrombins active-site is an effective target for inhibiting venous and arterial thrombosis, although venous thrombosis is more sensitive to this therapeutic strategy than arterial thrombosis.

HMG-CoA reductase inhibitors 4. Tetrazole series: conformational constraints and structural requirements at the hydrophobic domain.

Abstract Synthesis analogs 2–5 were prepared and the inhibitory activity was evaluated in order to assess the conformational constraints and the minimal structural requirements associated with the hydrophobic terminus of these tetrazole-derived dihydroxy acids for optimum potency.