Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases
Structure-activity relationship of atorvastatin derivatives for metabolic activation by hydrolases
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DOI：
10.1080/00498254.2019.1625083
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发表时间：
2019-06-15
期刊：
影响因子：
1.8
通讯作者：
Hosokawa, Masakiyo
中科院分区：
文献类型：
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作者：
Mizoi, Kenta;Takahashi, Masato;Hosokawa, Masakiyo
1. 以合成的31种阿托伐他汀酯类、硫酯类、酰胺类和内酯类药物为前药模型，研究了它们在微粒体和水解酶代谢激活下的构效关系。2. 人羧酸酯酶1 （hCES1）的易感性不仅受酰基和烷氧基大小的影响，还受烷氧基周围空间拥挤程度的影响。3. 对人羧酸酯酶2 （hCES2）的敏感性随着底物烷氧基周围电子密度的降低而增加。4. 内酯被对氧磷酶3 （PON3）特异性水解。5. 这些发现对控制代谢激活的前药设计有一定的指导意义。
1. We investigated the structure-activity relationship of 31 kinds of synthesized atorvastatin esters, thioesters, amides and lactone, selected as prodrug models, for metabolic activation by microsomes and hydrolases. 2. The susceptibility to human carboxylesterase 1 (hCES1) was influenced not only by the size of the acyl group and alkoxy group but also by the degree of steric crowding around the alkoxy group. 3. The susceptibility to human carboxylesterase 2 (hCES2) increased with a decrease in electron density around the alkoxy group of the substrate. 4. Lactone was specifically hydrolyzed by paraoxonase 3 (PON3). 5. These findings should be useful in prodrug design for controlling metabolic activation.