水溶性キモトリプシン阻害剤の合成研究(第2報)

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Water-soluble, substrate-analogous chymotrypsin inhibitors were synthesized to study the role of chymotrypsin and chymotrypsin-like enzymes in vivo. It was previously reported that the phenyl esters of carboxylic acids containing condensed ring such as tetralin, naphthalene, indole etc. showed potent inhibitory activity against chymotrypsin. In this report, the influence of several substituents on the benzene nucleus of phenyl component upon the inhibitory activity against enzymes was investigated. The esters derived from the phenol containing basic substituents in the 4 position (basic esters) exhibited potent inhibition against chymotrypsin, e.g. the IC_<50> value of 4-amidinophenyl tetralin-1-carboxylate was 5×10^<-7> M. But the activity of the ester obtained from the phenol containing neutral substituent in the 4 position (neutral ester) was weaker than that of the basic esters. The IC_<50> value of the neutral ester of the corresponding acyl component, 4-(N, N-dimethylcarbamoylmethoxycarbonylmethyl)phenyl tetralin-1-carboxylate was 7×10^<-6> M. And the acidic ester with carboxyl group on the benzene nucleus inhibited most weakly of the three, whose IC_<50> value was 6×10^<-5> M. With respect to the influence of these substituents, a similar tendency was observed in other esters derived from benzoic acid, 1-naphthylacetic acid, 3-indolylacetic acid etc. As for the influence of the acyl components on the inhibitory activity against chymotrypsin, the relative order was as follows : 5-methoxy-2-methyl-3-indolylacetyl≧1-naphthylacetyl≧tetralin-1-carbonyl>3-indolylacetyl>benzoyl. 4-(4-Guanidinobenzoyloxy)phenyl esters and 4-amidinophenyl esters inhibited not only chymotrypsin but also trypsin. On the other hand, the others such as 4-(4-isopropylpiperazinocarbonyl)phenyl esters inhibited chymotrypsin specifically.
社団法人日本薬学会の論文
1988-05-25

水溶性キモトリプシン阻害剤の合成研究(第2報)

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