Effects of steric hindrance and electron density of ester prodrugs on controlling the metabolic activation by human carboxylesterase

羧酸酯酶 前药 水解 位阻效应 化学 微粒体 烷氧基 酯水解 酯酶 新陈代谢 基质(水族馆) 氟比洛芬 药物化学 立体化学 烷基 有机化学 生物化学 生物 生态学 药理学
作者
Masato Takahashi,Ibuki Hirota,Tomoyuki Nakano,Tomoyuki Kotani,Daisuke Takani,Kana Shiratori,Yura Choi,Masami Haba,Masakiyo Hosokawa
出处
期刊:Drug Metabolism and Pharmacokinetics [Elsevier BV]
卷期号:38: 100391-100391 被引量:9
标识
DOI:10.1016/j.dmpk.2021.100391
摘要

Carboxylesterase (CES) plays an important role in the hydrolysis metabolism of ester–type drugs and prodrugs. In this study, we investigated the change in the hydrolysis rate of hCE1 by focusing on the steric hindrance of the ester structure and the electron density. For 26 kinds of synthesized indomethacin prodrugs, the hydrolytic rate was measured in the presence of human liver microsomes (HLM), human small intestine microsomes (HIM), hCE1 and hCE2. The synthesized prodrugs were classified into three types: an alkyl ester type that is specifically metabolized by hCE1, a phenyl ester type that is more easily metabolized by hCE1 than by hCE2, and a carbonate ester type that is easily metabolized by both hCE1 and hCE2. The hydrolytic rate of 1-methylpentyl (hexan–2–yl) ester was 10–times lower than that of 4–methylpentyl ester in hCE1 solution. hCE2 was susceptible to electron density of the substrate, and there was a difference in the hydrolysis rate of up to 3.5–times between p-bromophenyl ester and p-acetylphenyl ester. By changing the steric hindrance and electron density of the alkoxy group, the factors that change the hydrolysis rate by CES were elucidated.
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