NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - THE DISCOVERY OF A SERIES OF N-(BIPHENYLYLMETHYL)IMIDAZOLES AS POTENT, ORALLY ACTIVE ANTIHYPERTENSIVES
NONPEPTIDE ANGIOTENSIN-II RECEPTOR ANTAGONISTS - THE DISCOVERY OF A SERIES OF N-(BIPHENYLYLMETHYL)IMIDAZOLES AS POTENT, ORALLY ACTIVE ANTIHYPERTENSIVES
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DOI：
10.1021/jm00112a031
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发表时间：
1991-08-01
影响因子：
7.3
通讯作者：
TIMMERMANS, PBMWM
中科院分区：
文献类型：
--
作者：
CARINI, DJ;DUNCIA, JV;TIMMERMANS, PBMWM
合成了一系列新的非肽类血管紧张素Ⅱ（A Ⅱ）受体拮抗剂。 这些N-（联苯基-甲基）咪唑，例如2-丁基-1-[（2 '-羧基联苯基-4-基）甲基]-4-氯-5-（羟甲基）咪唑，与先前报道的N-（苯甲酰氨基苄基）咪唑和相关化合物的不同之处在于，它们在口服给药时产生有效的抗高血压作用;早期系列通常仅在静脉内给药时才有活性。 已经发现，在联苯的2 '-位上的酸性基团是必需的。 只有邻位取代的酸具有对AII受体的高亲和力和良好的口服抗高血压效力。 羧酸基团已被各种酸性电子等排体取代，并且已发现四唑环是最有效的。 四唑衍生物DuP 753目前正在开发用于治疗高血压。
A new series of nonpeptide angiotensin II (AII) receptor antagonists has been prepared. These N-(biphenylyl-methyl)imidazoles, e.g. 2-butyl-1-[(2'-carboxybiphenyl-4-yl)methyl]-4-chloro-5-(hydroxymethyl)imidazole, differ from the previously reported N-(benzamidobenzyl)imidazoles and related compounds in that they produce a potent antihypertensive effect upon oral administration; the earlier series generally were active only when administered intravenously. It has been found that the acidic group at the 2'-position of the biphenyl is essential. Only ortho-substituted acids possess both high affinity for the AII receptor and good oral antihypertensive potency. The carboxylic acid group has been replaced with a variety of acidic isosteres, and the tetrazole ring has been found to be the most effective. The tetrazole derivative, DuP 753, is currently in development for the treatment of hypertension.