Selective Inhibition of Carboxylesterases by Isatins, Indole-2,3-diones

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• 作者：Janice L. Hyatt ; Teri Moak ; M. Jason Hatfield ; Lyudmila Tsurkan ; Carol C. Edwards ; Monika Wierdl ; Mary K. Danks ; Randy M. Wadkins ; Philip M. Potter
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：April 19, 2007
• 年：2007
• 卷：50
• 期：8
• 页码：1876 - 1885
• 全文大小：350K
• 年卷期：v.50,no.8(April 19, 2007)
• ISSN：1520-4804

文摘

Carboxylesterases (CE) are ubiquitous enzymes thought to be responsible for the metabolism anddetoxification of xenobiotics. Numerous clinically used drugs including Demerol, lidocaine, capecitabine,and CPT-11 are hydrolyzed by these enzymes. Hence, the identification and application of selective CEinhibitors may prove useful in modulating the metabolism of esterified drugs in vivo. Having recentlyidentified benzil (diphenylethane-1,2-dione) as a potent selective inhibitor of CEs, we sought to evaluatethe inhibitory activity of related 1,2-diones toward these enzymes. Biochemical assays and kinetic studiesdemonstrated that isatins (indole-2,3-diones), containing hydrophobic groups attached at a variety of positionswithin these molecules, could act as potent, specific CE inhibitors. Interestingly, the inhibitory potency ofthe isatin compounds was related to their hydrophobicity, such that compounds with clogP values of <1.25were ineffective at enzyme inhibition. Conversely, analogs demonstrating clogP values >5 routinely yieldedK_i values in the nM range. Furthermore, excellent 3D QSAR correlates were obtained for two human CEs,hCE1 and hiCE. While the isatin analogues were generally less effective at CE inhibition than the benzils,the former may represent valid lead compounds for the development of inhibitors for use in modulatingdrug metabolism in vivo.