Synthesis and structure-activity relationships of human renin inhibitors designed from angiotensinogen transition state.
Synthesis and structure-activity relationships of human renin inhibitors designed from angiotensinogen transition state.
复制标题
从血管紧张素原过渡态设计的人肾素抑制剂的合成及其构效关系。
DOI：
10.1248/cpb.38.2487
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发表时间：
1990
影响因子：
1.7
通讯作者：
T. Yamaguchi
中科院分区：
文献类型：
--
作者：
K. Iizuka;T. Kamijo;H. Harada;K. Akahane;T. Kubota;Y. Etoh;I. Shimaoka;A. Tsubaki;M. Murakami;T. Yamaguchi
介绍了以血管紧张素原过渡态为原料设计的肾素抑制剂的合成及其构效关系。这些抑制剂含有在P1-P1 '、P2和P4-P3处修饰的残基。在P1时，去甲他汀类似物中侧链烷基的大小的减小降低了化合物的抑制活性。在P2处含有缬氨酸残基而不是组氨酸残基的化合物5 j有效地抑制组织蛋白酶D（IC 50 = 6.0 × 10（-9）M）和胃蛋白酶（IC 50 = 3.5 × 10（-7）M），抑制程度与肾素（IC 50 = 8.5 × 10（-10）M）相同，因此对肾素不是特异性的。P4-P3处β-羰基丙酰基残基中的β-羰基还原为亚甲基使对人肾素的效力降低约2个数量级（5i：IC 50 = 1.1 x 10（-7）M vs. 1：IC 50 = 2.4 x 10（-9）M）。这些结果证实了我们使用建模技术分析口服有效的人肾素抑制剂1与人肾素活性位点之间相互作用的合理性，表明1有利地适合于肾素的活性位点。合成的实验细节。
The synthesis and the structure-activity relationships of renin inhibitors designed from the angiotensinogen transition state are described. These inhibitors contained residues modified at P1-P1', P2, and P4-P3. Decrease in the size of side chain alkyl group in norstatine analog at P1 diminished the inhibitory activities of the compounds. Compound 5j, which contained valine residue instead of histidine residue at P2, inhibited potently cathepsin D (IC50 = 6.0 x 10(-9) M) and pepsin (IC50 = 3.5 x 10(-7) M) to the same extent as renin (IC50 = 8.5 x 10(-10) M), and thus was not specific for renin. The reduction of the beta-carbonyl group to methylene group in beta-carbonylpropionyl residue at P4-P3 decreased the potency about 2 orders against human renin (5i: IC50 = 1.1 x 10(-7) M vs. 1: IC50 = 2.4 x 10(-9) M). These results confirmed the rationality of our analysis of the interaction between an orally potent human renin inhibitor 1 and the active site of human renin using modeling techniques, showing that 1 fits the active site of renin favorably. The experimental details of the synthesis are presented.