前往化源商城

Journal of Medicinal Chemistry 2005-04-21

Identification and characterization of novel benzil (diphenylethane-1,2-dione) analogues as inhibitors of mammalian carboxylesterases.

Randy M Wadkins, Janice L Hyatt, Xin Wei, Kyoung Jin P Yoon, Monika Wierdl, Carol C Edwards, Christopher L Morton, John C Obenauer, Komath Damodaran, Paul Beroza, Mary K Danks, Philip M Potter

文献索引:J. Med. Chem. 48 , 2906-15, (2005)

全文:HTML全文

摘要

Carboxylesterases (CE) are ubiquitous enzymes responsible for the metabolism of xenobiotics. Because the structural and amino acid homology among esterases of different classes, the identification of selective inhibitors of these proteins has proved problematic. Using Telik's target-related affinity profiling (TRAP) technology, we have identified a class of compounds based on benzil (1,2-diphenylethane-1,2-dione) that are potent CE inhibitors, with K(i) values in the low nanomolar range. Benzil and 30 analogues demonstrated selective inhibition of CEs, with no inhibitory activity toward human acetylcholinesterase or butyrylcholinesterase. Analysis of structurally related compounds indicated that the ethane-1,2-dione moiety was essential for enzyme inhibition and that potency was dependent on the presence of, and substitution within, the benzene ring. 3D-QSAR analyses of these benzil analogues for three different mammalian CEs demonstrated excellent correlations of observed versus predicted K(i) (r(2) > 0.91), with cross-validation coefficients (q(2)) of 0.9. Overall, these results suggest that selective inhibitors of CEs with potential for use in clinical applications can be designed.

相关化合物

结构式 名称/CAS号 全部文献
二苯甲酮 结构式 二苯甲酮
CAS:119-61-9
7-乙酰氧基-4-甲基香豆素 结构式 7-乙酰氧基-4-甲基香豆素
CAS:2747-05-9
四氯对醌 结构式 四氯对醌
CAS:118-75-2
3-甲基-1,2-环戊二酮 结构式 3-甲基-1,2-环戊二酮
CAS:765-70-8
甲基环戊烯醇酮 结构式 甲基环戊烯醇酮
CAS:80-71-7
乙酰丙酮 结构式 乙酰丙酮
CAS:123-54-6
苯醌 结构式 苯醌
CAS:106-51-4
2-羟基-2-苯基苯乙酮 结构式 2-羟基-2-苯基苯乙酮
CAS:119-53-9
1-苯基-1,2-丙二酮 结构式 1-苯基-1,2-丙二酮
CAS:579-07-7
4-苯甲酰苯甲酸 结构式 4-苯甲酰苯甲酸
CAS:611-95-0