|
Renin inhibitors are a group of pharmaceutical drugs used primarily in treatment of essential hypertension (high blood pressure). These drugs inhibit the first and rate-limiting step of the renin–angiotensin–aldosterone system (RAAS), namely the conversion of angiotensinogen to angiotensin I.This leads to a totality in absence of Angiotensin II based on the rationale that renin only acts to inhibit this step unlike Angiotensin Converting Enzyme which is also involved in other biochemical reactions. Since the 1970s, scientists have been trying to develop potent inhibitors with acceptable oral bioavailability. The process was difficult and took about three decades. The first and second generations faced problems such as poor bioavailability and lack of potency. Finally, the third generation was discovered. These compounds were nonpeptidic renin inhibitors, had acceptable oral bioavailability and were potent enough for clinical use. The first drug in this class was aliskiren, which received a marketing approval in 2007.〔 , it is the only renin inhibitor on the market. == History == In 1896, the Finnish physiologist Robert Tigerstedt and the Swedish physician Per Bergman did an experiment on kidneys and the circulatory system in rabbits. They observed that blood pressure rose in the rabbits when extracts of the kidneys were injected into their jugular veins. They also discovered this substance responsible for higher blood pressure was produced in the renal cortex, and they named it renin.〔 Although this experiment laid the foundation for future investigations into the RAAS pathway, it had little impact on the scientific community at that time.〔 In 1934, when Goldblatt published his work in renal ischaemia, renin came into focus again. The importance of renin in the pathogenesis of cardiovascular disease was, however, not fully understood until in the 1970s, and 20 years later the first renin inhibitors went to clinical trials.〔 Pepstatin, which was described in 1972, was the first synthetic renin inhibitor, but poor pharmacokinetic properties prevented it from entering ''in vivo'' investigations.〔 The first generation of renin inhibitors, such as H-142, were peptide analogues of angiotensinogen. However, these inhibitors had also limited drug-like properties.〔〔 Hopes of breakthrough appeared in 1982 when development of the second generation renin inhibitors began.〔 This generation consisted of peptide-like compounds, such as remikiren, enalkiren and zanikiren.〔 They had more drug-like rather than substrate-like properties, and in 1990 they went to clinical trials. The second generation had its limitations and never completed clinical trials.〔 Aliskiren, the only renin inhibitor to go into phase III clinical trials, is not structurally related to peptides, which makes it a third-generation renin inhibitor.〔 The first clinical trial was performed in 2000 in healthy volunteers. In 2007, aliskiren was approved by the US Food and Drug Administration and the European Medicines Agency as a treatment for hypertension.〔 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「Renin inhibitor」の詳細全文を読む スポンサード リンク
|