ACTIVE-SITE-DIRECTED THROMBIN INHIBITORS - ALPHA-HYDROXYACYL-PROLYL-ARGINALS, NEW ORALLY-ACTIVE STABLE ANALOGS OF D-PHE-PRO-ARG-H

D-alpha-Hydroxyacyl-prolyl-arginals, anew type of analogues of D-Phe-P ro-Arg-H (R1), have been prepared and evaluated. Unlike R1, whose term inal group is NH2, the new analogues with a terminal OH group are stab le, as are the N-substituted derivatives of R1, that is, D-MePhe-Pro-A rg-H (R2), the highly potent and selective thrombin inhibitor, and Boc -D-Phe-Pro-Arg-H (R3), the much less favorable analogue. The most nota ble of the new analogues corresponds to the general formula D-Xaa-Pro- Arg-H, wherein Xaa means the acyl residue of mandelic acid (Man, 1), d iphenyllactic acid (Dpl, 2), hexahydro-phenyllactic acid (Hpl, 3), or hexahydromandelic acid (Hma, 4). In plasma clotting assays, 1 to 4 app eared to inhibit thrombin as,cell as some other clotting enzymes invol ved in thrombin generation, whereas R1 and R2 seemed to produce antico agulation through inhibition of thrombin only. In the fibrin plate ass ay, 1 to 4 possessed even more moderate antifibrinolytic activities th an R2. In in vivo evaluation in rats and rabbits, 2 to 4 proved to be potent anticoagulants/ antithrombotics even on oral administration in a dose of 5 mg/kg. In view of these findings with the alpha-hydroxyacy l-prolyl-arginals, it is very likely that the less favorable biologic properties of Boc-D-Phe-Pro-Arg-H are due to the hydrophobicity and bu lkiness of the terminal Boc-NH rather than its neutrality.