Novel S-Adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis
Novel S-Adenosylmethionine Decarboxylase Inhibitors for the Treatment of Human African Trypanosomiasis
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DOI：
10.1128/aac.01674-08
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发表时间：
2009-05-01
影响因子：
4.9
通讯作者：
Sybertz, Edmund
中科院分区：
文献类型：
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作者：
Barker, Robert H., Jr.;Liu, Hanlan;Sybertz, Edmund
锥虫病仍然是撒哈拉以南非洲大陆的一种严重疾病，有50，000至70，000人被感染。目前疗法的效用受到毒性问题和静脉内施用化合物的需要的限制。我们已经开始了一项计划，以追求围绕MDL 73811的铅优化，MDL 73811是一种S-腺苷甲硫氨酸脱羧酶（SNAMetDC）的不可逆抑制剂。这种化合物是有效的，但在以前的研究中，从大鼠的血液中迅速清除（T。L. Byers，T. L. Bush，P. P. McCann，and A. J. Bitonti，Biochem. J. 274：527-533）。合成的类似物之一（Genz-644131）显示在体外对布氏罗得西亚锥虫具有高度活性（50%抑制浓度，400 pg/ml）。酶动力学研究表明，Genz-644131对T.布氏杆菌MetDC-酶原复合物。该化合物在体外大鼠和人肝微粒体和肝细胞试验中稳定，在大鼠全血试验中稳定，未显著抑制人细胞色素P450酶，在CaCo-2细胞中无可测量的外排，仅41%与血清蛋白结合。小鼠腹腔内给药后的药效学研究表明，Genz-644131的半衰期是MDL 73811的三倍（7.4小时与2.5小时）。此外，Genz-644131的脑渗透性是MDL 73811的4.3倍。最后，对T. B.感染布氏菌株STIB 795的小鼠显示，Genz-644131显著延长了存活期（从对照组的6.75天延长到治疗组的> 30天），并且治愈了感染T. B.布氏杆菌菌株LAB 110 EATRO。总而言之，这些数据加强了AdoMetDC作为重要寄生虫靶点的验证，并且这些研究表明，MDL 73811的类似物可以合成为具有更高的效力和脑渗透性。
Trypanosomiasis remains a significant disease across the sub-Saharan African continent, with 50,000 to 70,000 individuals infected. The utility of current therapies is limited by issues of toxicity and the need to administer compounds intravenously. We have begun a program to pursue lead optimization around MDL 73811, an irreversible inhibitor of S-adenosylmethionine decarboxylase (AdoMetDC). This compound is potent but in previous studies cleared rapidly from the blood of rats (T. L. Byers, T. L. Bush, P. P. McCann, and A. J. Bitonti, Biochem. J. 274:527-533). One of the analogs synthesized (Genz-644131) was shown to be highly active against Trypanosoma brucei rhodesiense in vitro (50% inhibitory concentration, 400 pg/ml). Enzyme kinetic studies showed Genz-644131 to be approximately fivefold more potent than MDL 73811 against the T. brucei brucei AdoMetDC-prozyme complex. This compound was stable in vitro in rat and human liver microsomal and hepatocyte assays, was stable in rat whole-blood assays, did not significantly inhibit human cytochrome P450 enzymes, had no measurable efflux in CaCo-2 cells, and was only 41% bound by serum proteins. Pharmaco-kinetic studies of mice following intraperitoneal dosing showed that the half-life of Genz-644131 was threefold greater than that of MDL 73811 (7.4 h versus 2.5 h). Furthermore, brain penetration of Genz-644131 was 4.3-fold higher than that of MDL 73811. Finally, in vivo efficacy studies of T. b. brucei strain STIB 795-infected mice showed that Genz-644131 significantly extended survival (from 6.75 days for controls to > 30 days for treated animals) and cured animals infected with T. b. brucei strain LAB 110 EATRO. Taken together, the data strengthen validation of AdoMetDC as an important parasite target, and these studies have shown that analogs of MDL 73811 can be synthesized with improved potency and brain penetration.