Waga T, Matsui S, Saito S, Watanabe M, Kajiwara Y, Shirota M, Iijima M, Kitabatake K
Central Research Laboratories, Asahi Breweries, Ltd., Tokyo, Japan.
Arzneimittelforschung. 1990 Apr;40(4):407-13.
The synthesis of a series of novel, potent angiotensin converting enzyme (ACE) inhibitors containing 1(S)-carboxy-omega-(4-piperidyl)alkyl group at the N-terminal of the dipeptide is described. These 1-carboxy-omega-(4-piperidyl)alkyl derivatives possess greater or equivalent in vitro potency and in vivo efficacy than captopril and enalapril. The length (n) of the carbon chain in the omega-(4-piperidyl)alkyl moiety was varied from two to six to investigate the optimal structure for long-acting ACE inhibitors. 1-[N-[1(S)-Carboxy-6-(4- piperidyl)hexyl]-L-alanyl]-(2a,3a beta, 7a beta)-octahydro- 1H-indole-2-carboxylic acid (9b), the most potent member of the series, had an in vivo area under the curve (AUC) of 685, which was calculated by the inhibition of angiotensin I-induced pressor response vs. time curves (0 to 8 h) after p.o. administration.
本文描述了一系列新型强效血管紧张素转换酶（ACE）抑制剂的合成，这些抑制剂在二肽的N端含有1(S)-羧基-ω-(4-哌啶基)烷基。这些1-羧基-ω-(4-哌啶基)烷基衍生物在体外效力和体内疗效方面比卡托普利和依那普利更强或相当。改变ω-(4-哌啶基)烷基部分碳链的长度（n），范围从2到6，以研究长效ACE抑制剂的最佳结构。该系列中最有效的成员1-[N-[1(S)-羧基-6-(4-哌啶基)己基]-L-丙氨酰]-(2a,3aβ,7aβ)-八氢-1H-吲哚-2-羧酸（9b），经口服给药后，通过抑制血管紧张素I诱导的升压反应与时间曲线（0至8小时）计算得出其体内曲线下面积（AUC）为685。
