A Series of Extremely Potent Thrombin-Inhibitors Newly Synthetized

Starting with the simple arginine derivatives having weak thrombin-inhibitory activity, ca. 320 chemical compounds were designed and synthetized by the authors, in such a way as increasing the inhibitory activity by stepwise chemical modifications. The extremely potent inhibitors thus obtained are described.

These inhibitors are chemcially naphthalene-sulfonyl-arginine derivatives, the basic structure being composed of three functional sub-units and designed, to reflect the part of fibrinogen peptide to be split by thrombin.

One of the representatives, dansyl-arginine-ethyl-piperidine amide, inhibited 50% of thrombin activity at 0.1 μM when 5 μM fibrinogen was substrate. Similar result was also obtained when benzoyl-Phe-Val-Arg-pNA was substrate. The mode of inhibition was found competitive.

The inhibitors suppressed the platelets aggregation due to thrombin satisfactorily. However, the inhibition on plasmin, reptilase or trypsin was far weaker, indicating the very high selectivity to thrombin. Their relatively low toxicity led the authors to extend the studies toward the animal experiments and results obtained will be reported elsewhere.