Barker Robert H, Liu Hanlan, Hirth Bradford, Celatka Cassandra A, Fitzpatrick Richard, Xiang Yibin, Willert Erin K, Phillips Margaret A, Kaiser Marcel, Bacchi Cyrus J, Rodriguez Aixa, Yarlett Nigel, Klinger Jeffrey D, Sybertz Edmund
Genzyme Corporation, 153 Second Avenue, Waltham, MA 02451, USA.
Antimicrob Agents Chemother. 2009 May;53(5):2052-8. doi: 10.1128/AAC.01674-08. Epub 2009 Mar 16.
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. Pharmacokinetic 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.
在撒哈拉以南非洲大陆，锥虫病仍然是一种重要疾病，有5万至7万人受到感染。当前疗法的效用受到毒性问题以及需要静脉注射化合物的限制。我们已经启动了一个项目，围绕MDL 73811进行先导化合物优化，MDL 73811是S-腺苷甲硫氨酸脱羧酶（AdoMetDC）的不可逆抑制剂。该化合物效力很强，但在先前研究中从大鼠血液中清除迅速（T. L. Byers、T. L. Bush、P. P. McCann和A. J. Bitonti，《生物化学杂志》274:527 - 533）。合成的一种类似物（Genz-644131）在体外对布氏罗得西亚锥虫显示出高活性（50%抑制浓度，400 pg/ml）。酶动力学研究表明，Genz-644131对布氏布氏锥虫AdoMetDC - 酶原复合物的效力比MDL 73811高约五倍。该化合物在大鼠和人肝微粒体及肝细胞试验中体外稳定，在大鼠全血试验中稳定，不显著抑制人细胞色素P450酶，在CaCo - 2细胞中无明显外排，且仅41%与血清蛋白结合。对小鼠腹腔给药后的药代动力学研究表明，Genz-644131的半衰期比MDL 73811长三倍（7.4小时对2.5小时）。此外，Genz-644131的脑渗透率比MDL 73811高4.3倍。最后，对感染布氏布氏锥虫STIB 795株的小鼠进行的体内疗效研究表明，Genz-644131显著延长了生存期（从对照组的6.75天延长至治疗动物的>30天），并治愈了感染布氏布氏锥虫LAB 110 EATRO株的动物。综上所述，这些数据加强了对AdoMetDC作为重要寄生虫靶点的验证，并且这些研究表明可以合成出效力和脑渗透率更高的MDL 73811类似物。
