Active site-directed thrombin inhibitors: α-hydroxyacylprolyl-arginals. New orally active stable analogs of d-Phe-Pro-Arg-H Original Research Article

d-α-Hydroxyacyl-prolyl-arginals have been designed and synthesized as orally active stable analogs of d-Phe-Pro-Arg-H, the active site-directed peptidyl thrombin inhibitor prototype. Many of the new analogs possess high in vitro anticoagulant activity while having little effect on fibrinolysis. Compounds GYKI-66104 (2), −66131 (3) and −66132 (5) effectively delay the clotting time in rabbits ex vivo and prevent thrombus formation in various thrombosis models in rabbits and rats when applied in a single oral dose of 5 mg kg−1