Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) toxicity.
Improved, selective, human intestinal carboxylesterase inhibitors designed to modulate 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (Irinotecan; CPT-11) toxicity.
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DOI：
10.1021/jm9001296
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发表时间：
2009-06-25
影响因子：
7.3
通讯作者：
Potter PM
中科院分区：
文献类型：
--
作者：
Hicks LD;Hyatt JL;Stoddard S;Tsurkan L;Edwards CC;Wadkins RM;Potter PM
CPT-11是一种抗肿瘤前药，可被羧酸酯酶（CE）水解产生SN-38，一种强效拓扑异构酶I毒物。然而，剂量限制性毒性是延迟性腹泻，其被认为部分由人肠CE（hiCE）激活前药引起。因此，我们已经寻求鉴定可能在调节药物毒性中具有效用的hiCE的选择性抑制剂。我们已经评估了这样一类分子（苯磺酰胺类），并开发了抑制这种蛋白质的QSAR模型。使用这些预测模型，我们合成了一组芴类似物，它们对hiCE具有选择性，与人肝CE、hCE 1或人胆碱酯酶没有交叉反应性，Ki值低至14 nM。这些化合物阻止了hiCE介导的药物水解，并且酶抑制效力与分子的clogP相关。这些研究将允许开发和应用hiCE特异性抑制剂，旨在选择性地调节体内药物水解。
CPT-11 is an antitumor prodrug that is hydrolyzed by carboxylesterases (CE) to yield SN-38, a potent topoisomerase I poison. However, the dose limiting toxicity is delayed diarrhea that is thought to arise, in part, from activation of the prodrug by a human intestinal CE (hiCE). Therefore, we have sought to identify selective inhibitors of hiCE that may have utility in modulating drug toxicity. We have evaluated one such class of molecules (benzene sulfonamides), and developed QSAR models for inhibition of this protein. Using these predictive models, we have synthesized a panel of fluorene analogues that are selective for hiCE, demonstrating no cross reactivity to the human liver CE, hCE1, or towards human cholinesterases, and have Ki values as low as 14nM. These compounds prevented hiCE-mediated hydrolysis of the drug and the potency of enzyme inhibition correlated with the clogP of the molecules. These studies will allow the development and application of hiCE-specific inhibitors designed to selectively modulate drug hydrolysis in vivo.
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DOI：
10.1124/jpet.106.111807
发表时间：
2006-12-01
影响因子：
3.5
作者：
Shi, Deshi;Yang, Jian;Yan, Bingfang
通讯作者：
Yan, Bingfang
影响因子：
4.8
作者：
Pindel, EV;Kedishvili, NY;Bosron, WF
通讯作者：
Bosron, WF
影响因子：
7.3
作者：
Hyatt, JL;Stacy, V;Potter, PM
通讯作者：
Potter, PM
影响因子：
3.5
作者：
Hicks, Latorya D.;Hyatt, Janice L.;Potter, Philip M.
通讯作者：
Potter, Philip M.
影响因子：
7.3
作者：
Hyatt, Janice L.;Moak, Teri;Potter, Philip M.
通讯作者：
Potter, Philip M.