Boger J, Lohr N S, Ulm E H, Poe M, Blaine E H, Fanelli G M, Lin T Y, Payne L S, Schorn T W, LaMont B I, Vassil T C, Stabilito I I, Veber D F, Rich D H, Bopari A S
Nature. 1983;303(5912):81-4. doi: 10.1038/303081a0.
The proteolytic enzyme renin (EC3.4.99.19) cleaves the protein substrate angiotensinogen to yield angiotensin I, the decapeptide substrate transformed by converting enzyme into the pressor substance angiotensin II. Although the contribution of this pathway to the maintenance of normal blood pressure is unclear, it seems to be a major factor in various hypertensive states. Important progress in the control of hypertension has been achieved by development of the potent inhibitors SQ-14,225 (captopril) and MK-421 (enalapril maleate), which block the generation of angiotensin II by the inhibition of angiotensin converting enzyme. An attractive alternative to the inhibition of converting enzyme would be the blockade of the preceding step in the cascade, the renin reaction. We report here new highly potent (IC50 = 10(-9)-10(-8) M) competitive inhibitors of renin in which statine, (3S,4S)-4-amino-3-hydroxy-6-methylheptanoic acid, is incorporated into analogues of the pig renin substrate (Fig. 1).
蛋白水解酶肾素（EC3.4.99.19）可切割蛋白质底物血管紧张素原，生成血管紧张素I，这种十肽底物会被转换酶转化为升压物质血管紧张素II。尽管该途径对维持正常血压的作用尚不清楚，但它似乎是各种高血压状态下的一个主要因素。通过开发强效抑制剂SQ - 14,225（卡托普利）和MK - 421（马来酸依那普利），在高血压控制方面取得了重要进展，这些抑制剂通过抑制血管紧张素转换酶来阻断血管紧张素II的生成。抑制转换酶的一种有吸引力的替代方法是阻断级联反应的前一步，即肾素反应。我们在此报告了新型高效（IC50 = 10(-9)-10(-8) M）的肾素竞争性抑制剂，其中在猪肾素底物类似物中引入了他汀（(3S,4S)-4-氨基-3-羟基-6-甲基庚酸）（图1）。
