Yanagisawa H, Amemiya Y, Kanazaki T, Shimoji Y, Fujimoto K, Kitahara Y, Sada T, Mizuno M, Ikeda M, Miyamoto S, Furukawa Y, Koike H
Research Institute, Sankyo Company, Ltd., Tokyo, Japan.
J Med Chem. 1996 Jan 5;39(1):323-38. doi: 10.1021/jm950450f.
A series of imidazole-5-carboxylic acids bearing alkyl, alkenyl, and hydroxyalkyl substituents at the 4-position and their related compounds were prepared and evaluated for their antagonistic activities to the angiotensin II (AII) receptor. Among them, the 4-(1-hydroxyalkyl)-imidazole derivatives had strong binding affinity to the AII receptor and potently inhibited the AII-induced pressor response by intravenous administration. Various esters of these acids showed potent and long-lasting antagonistic activity by oral administration. The most promising compounds were (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl (CS-866) and (pivaloyloxy)-methyl esters of 4-(1-hydroxy-1-methylethyl)-2-propyl-1-[(2'-1H-tetrazol-5- ylbiphenyl-4-yl)-methyl]imidazole-5-carboxylic acid (26c). A study involving stereochemical comparison of 26c with the acetylated C-terminal pentapeptide of AII was also undertaken.
制备了一系列在4位带有烷基、烯基和羟烷基取代基的咪唑-5-羧酸及其相关化合物，并评估了它们对血管紧张素II（AII）受体的拮抗活性。其中，4-(1-羟烷基)-咪唑衍生物对AII受体具有很强的结合亲和力，并通过静脉给药有效抑制AII诱导的升压反应。这些酸的各种酯通过口服给药显示出强效且持久的拮抗活性。最有前景的化合物是(5-甲基-2-氧代-1,3-二氧戊环-4-基)甲基（CS-866）和4-(1-羟基-1-甲基乙基)-2-丙基-1-[(2'-1H-四唑-5-基联苯-4-基)-甲基]咪唑-5-羧酸的(新戊酰氧基)甲酯（26c）。还进行了一项涉及26c与AII乙酰化C末端五肽的立体化学比较的研究。
