Structure-activity relationship in a series of synthetic thrombin inhibitors: No. 205, No. 407 and No. 700

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• A series of synthetic thrombin inhibitors, reported by us in 1975, exerted an extremely potent and highly selective inhibition on thrombin. In case of the compound No. 205 (dansyl-L-arginine-ethylpiperidine amide), I50 for thrombin was 0.1μM; however, LD50 was 80mg/kg i. p. in mice.A compound No. 407, found by us in 1977, was characterized by its low toxicity (LD50: 900mg/kg i. p. in mice); I50 for thrombin was 0.3μM. Distribution volume of No. 407, calculated from its decreasing curve in plasma, was far smaller than that of No. 205, indicating the improved property for in vivo use.Since then, approximately 400 new compounds were synthesized by us and several very active compounds (I50:≤0.3μM) were obtained. It was noticed that all of the active compounds assumed the same basic structure; that is, they took tri-pod structure, one leg being L-arginine; another, aromatic; and the other, hydrophobic.Results obtained also indicated that none of the homologues derived from D-arginine (such as dansyl-D-arginine-butylamide) exerted inhibition. CH2 chain between α-carbon and guanidino groups of arginine could not be chemically changed without losing the inhibitory activity.As to the hydrophobic and aromatic parts of our tri-pod inhibitors the possibility for successful chemical modification (without losing the inhibitory activity) was strictly limited.Results accumulated from ca. 800 arginine derivatives indicated that "stereogeometry" of the active site of thrombin was so strictly defined that the enzyme could select the natural substrates with high accuracy.Finally, No. 700 type inhibitors, in which α-NH2 of arginine was protected by quinoline derivatives, should be added in present report because I50 of No. 700 for thrombin was very small beyond expectation.

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一般社団法人 日本血栓止血学会 | 論文

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