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肾素-血管紧张素系统(RAS)的第一步及限速的蛋白水解反应,是血管紧张素原的N末端在肾素的酶促作用下水解为血管紧张素I(AI).对该步的抑制有高度特异性,而对血管紧张素转换酶(ACE)的抑制为非特异性.长期以来,肾素的高特异性吸引了众多药理学家及药物化学家,但也为设计可作药用的肾素抑制剂带来不少问题.例如,ACE的底物可小至酰化的三肽,而肾素的已知最小底物是八肽(化合物1,见表1).因此,似乎肾素抑制剂也必须较大,这就产生了代谢、生物利用度及作用时间方面的问题.故至今口服生物利用度高,
The first and rate-limiting proteolytic response of the renin-angiotensin system (RAS) is the hydrolysis of angiotensinogen N-terminal to angiotensin I (AI) under the enzymatic action of renin The inhibition of the steps is highly specific and the inhibition of angiotensin converting enzyme (ACE) is nonspecific. The high specificity of renin has long attracted many pharmacologists and medicinal chemists, but it is also designed for For example, the substrate for ACE can be as small as the acylated tripeptide, while the smallest known substrate for renin is the octapeptide (Compound 1, see Table 1). Thus, , It seems that the renin inhibitor must also be larger, which resulted in metabolic, bioavailability and role of the time the problem.So so far oral bioavailability,