PEPSTATIN ANALOGS AS NOVEL RENIN INHIBITORS
PEPSTATIN ANALOGS AS NOVEL RENIN INHIBITORS
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DOI：
10.1021/jm00157a006
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发表时间：
1986-07-01
影响因子：
7.3
通讯作者：
ROQUES, BP
中科院分区：
文献类型：
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作者：
GUEGAN, R;DIAZ, J;ROQUES, BP
在溶液相中合成了通式为A-X-Y-Sta-Ala-Sta-R的胃抑素类似物。对A、X和Y基团的性质进行了各种改变，以提高对人血浆肾素活性的抑制效力。结果用基于人血管紧张素原序列的活性部位模型来解释。叔丁氧基和异戊基是最有效的酰基(A)。用Phe残基取代Val1(X)和他或Y位含有脂肪族侧链的氨基酸，如去甲亮氨酸或去甲丙氨酸，对人血浆肾素活性的抑制作用最强，IC50值约为108M。他汀类药物C-末端的羧基的酯化或酰胺化不改变抑制作用。研究了最有趣的化合物对大鼠、狗、猪和猴子血浆肾素的选择性。
Pepstatin analogues corresponding to the general formula A-X-Y-Sta-Ala-Sta-R were synthesized in solution phase. Various changes in the nature of the A, X, and Y groups were made to improve the inhibitory potency against human plasma renin activity. The results were interpreted by use of the active-site model based on the sequence of human angiotensinogen. The tert-butyloxycarbonyl group and the isovaleryl group were found to be the most effective acyl groups (A). The analogues having a Phe residue in place of Val1 (X) and His or an amino acid with an aliphatic side chain such as norleucine or norvaline in the Y position showed the highest inhibition of human plasma renin activity with IC50 values of about 108 M. Esterification or amidification of the carboxyl group of the C-terminal statin did not change the inhibitory potency. The selectivity for rat, dog, pig, and monkey plasma renin of the most interesting compounds was studied.