NEW INHIBITORS OF HUMAN RENIN THAT CONTAIN NOVEL LEU-VAL REPLACEMENTS
NEW INHIBITORS OF HUMAN RENIN THAT CONTAIN NOVEL LEU-VAL REPLACEMENTS
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DOI：
10.1021/jm00392a015
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发表时间：
1987-09-01
影响因子：
7.3
通讯作者：
PLATTNER, JJ
中科院分区：
文献类型：
--
作者：
LULY, JR;YI, N;PLATTNER, JJ
提出了几种非肽片段的立体选择性合成，这些非肽片段在人血管紧张素原中充当 Leu10-Val11 断裂键替代物。 N-保护的氨基烷基环氧化物3与各种硫、氧、氮和碳亲核试剂的开环是制备这些新片段4-8的关键反应。这些片段与模拟血管紧张素原中第 8 和 9 位的受保护二肽偶联，产生人肾素抑制剂，尽管这些分子不包含除血管紧张素原形式上的 Val11 侧链之外的功能。优选与Val侧链非常相似的R基团；因此，异丙基.gtoreq。高级烷基<苯基<取代的苯基。硫是最好的X基团；氧化导致抑制效力轻微（X = SO2）和显着（X = SO）下降。其中一种抑制剂 60 在 pH 6.0 下用纯化的人肾素进行测试时，IC50 为 13 nM。这些小抑制剂的显着活性被认为部分归因于充当过渡态类似物的片段的羟基。其中，含有组氨酸的抑制剂对肾素表现出比相关天冬氨酸蛋白酶、胃蛋白酶显着的选择性。
Stereoselective syntheses of several nonpeptide fragments that functions as Leu10-Val11 scissile bond replacements in human angiotensinogen are presented. The opening of N-protected aminoalkyl epoxide 3 with a variety of sulfur, oxygen, nitrogen, and carbon nucleophiles is a key reaction in the preparation of these novel fragments 4-8. The coupling of these fragments to protected dipeptides that mimic positions 8 and 9 in angiotensinogen produces inhibitors of human renin even though the molecules contain no functionality beyond what is formally the Val11 side chain of angiotensinogen. R groups that closely resemble that of the Val side chain are preferable; thus, isopropyl .gtoreq. higher alkyl < phenyl < substituted phenyl. Sulfur is the best X group; oxidation leads to slight (X = SO2) and significant (X = SO) decrease in inhibitory potency. One such inhibitor, 60, has an IC50 of 13 nM when tested with purified human renin at pH 6.0. The significant activity of these small inhibitors is thought to be due in part to the hydroxyl group of the fragment functioning as a transition-state analogue. Of these, the inhibitors that contain histidine show marked selectivity toward renin over a related aspartic proteinase, pepsin.