[(氨甲基)芳氧基]乙酸酯。一类新型的高效能利尿剂。2. 氧乙酸侧链的修饰。
[(Aminomethyl)aryloxy]acetic acid esters. A new class of high-ceiling diuretics. 2. Modifications of the oxyacetic side chain.
作者信息
Plattner J J, Fung A K, Smital J R, Lee C M, Crowley S R, Pernet A G, Bunnell P R, Buckner S A, Sennello L T
出版信息
J Med Chem. 1984 Dec;27(12):1587-96. doi: 10.1021/jm00378a011.
The discovery of high-ceiling natriuretic activity from a series of aminomethyl derivatives of ethyl [2,3-dichloro-4-(4-hydroxybenzoyl)phenoxy]acetate prompted our continued investigation of this new class of (aryloxy)acetic acid diuretics. Systematic alteration of the oxyacetic side chain has shown that the carboxylic acid function is the active species in vivo and that the ethyl ester group serves as a prodrug to enhance oral absorption. Side-chain functional groups that are incapable of generating the carboxylic acid in vivo failed to impart diuretic activity to the target compounds. Additional side-chain modifications including homologation, methyl substitution, and heteroatom replacement are also described. Ring annelation of the oxyacetic side chain to a dihydrobenzofuran-2-carboxylic acid produced compound 32, which displayed the highest level of saluretic activity for this series.
从一系列[2,3-二氯-4-(4-羟基苯甲酰基)苯氧基]乙酸乙酯的氨甲基衍生物中发现了高效的利钠活性，这促使我们继续研究这类新型的（芳氧基）乙酸利尿剂。对氧乙酸侧链进行系统改造表明，羧酸官能团是体内的活性物质，而乙酯基团作为前药可增强口服吸收。体内无法生成羧酸的侧链官能团无法赋予目标化合物利尿活性。还描述了包括同系化、甲基取代和杂原子取代在内的其他侧链修饰。将氧乙酸侧链环合到二氢苯并呋喃-2-羧酸上得到化合物32，该化合物在该系列中显示出最高水平的促尿钠排泄活性。
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