NEW N-ALPHA-GUANIDINOBENZOYL DERIVATIVES OF HIRUDIN-54-65 CONTAINING STABILIZED CARBOXYL OR PHOSPHORYL GROUPS ON THE SIDE-CHAIN OF PHENYLALANINE-63

We report on the synthesis and pharmacological properties of a new ser ies of thrombin inhibitors derived from hirudin carboxyl-terminal frag ments. Two (arylphosphono)phenylalanines, p-PO3H2-L-phe(1) and m-PO3H2 -L-Tyr, and one (carboxymethyl)phenylalanine, p-CH2COOH-L-Phe, were pr epared and incorporated into position 63 of the modified hirudin's C-t erminal dodecapeptide using the Fmoc solid-phase synthesis strategy. S ubstitution by any one of the residues led to very active analogs whic h doubled the thrombin time at low micromolar concentration (C-tt2 in vitro (1 mu M < C-tt2 < 3 mu M) and potently increased the activated p artial thromboplastin time (APTT) ex vivo. These compounds displayed a higher potency in vitro and a longer duration of action in vivo than both the corresponding sulfated or phosphorylated tyrosine counterpart s.