A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.
A long-duration dihydroorotate dehydrogenase inhibitor (DSM265) for prevention and treatment of malaria.
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DOI：
10.1126/scitranslmed.aaa6645
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发表时间：
2015-07-15
影响因子：
17.1
通讯作者：
Charman SA
中科院分区：
文献类型：
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作者：
Phillips MA;Lotharius J;Marsh K;White J;Dayan A;White KL;Njoroge JW;El Mazouni F;Lao Y;Kokkonda S;Tomchick DR;Deng X;Laird T;Bhatia SN;March S;Ng CL;Fidock DA;Wittlin S;Lafuente-Monasterio M;Benito FJ;Alonso LM;Martinez MS;Jimenez-Diaz MB;Bazaga SF;Angulo-Barturen I;Haselden JN;Louttit J;Cui Y;Sridhar A;Zeeman AM;Kocken C;Sauerwein R;Dechering K;Avery VM;Duffy S;Delves M;Sinden R;Ruecker A;Wickham KS;Rochford R;Gahagen J;Iyer L;Riccio E;Mirsalis J;Bathhurst I;Rueckle T;Ding X;Campo B;Leroy D;Rogers MJ;Rathod PK;Burrows JN;Charman SA
疟疾是导致儿童死亡的最重要原因之一，但疟疾寄生虫对当前治疗方法的抗药性威胁着疾病控制工作。在防治疟疾方面继续取得进展，需要开发新的、易于管理的药物组合，具有针对该疾病所有表现形式的广泛活性。DSM265是一种以三唑并嘧啶为基础的嘧啶生物合成酶二氢罗酸脱氢酶(DHODH)抑制剂，是第一个达到临床开发的用于治疗疟疾的DHODH抑制剂。我们描述了DSM265的生物活性、药理和药代动力学特性以及安全性的研究，这些研究支持它进入人体试验。DSM265对疟疾原虫的DHODH具有高度的选择性，对恶性疟原虫的血液和肝脏阶段都有效，对耐药的寄生虫分离株也有活性。DSM265良好的药代动力学特性被预测为在单次口服200-400毫克剂量后提供超过8天的治疗浓度。DSM265在小鼠和狗的重复给药和心血管安全性研究中耐受性良好，没有诱变性，对人酶/受体面板没有活性。DSM265具有良好的安全性、血液和肝脏阶段的活性，并预测了较长的人类半衰期，DSM265将成为新的潜在药物组合伙伴，用于单剂量治疗或每周一次的化学预防。DSM265比目前每天给药或在寄生虫肝期不活跃的治疗方案更具优势
Malaria is one of the most significant causes of childhood mortality but disease control efforts are threatened by resistance of the Plasmodium parasite to current therapies. Continued progress in combating malaria requires development of new, easy to administer drug combinations with broad ranging activity against all manifestations of the disease. DSM265, a triazolopyrimidine-based inhibitor of the pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH), is the first DHODH inhibitor to reach clinical development for treatment of malaria. We describe studies profiling the biological activity, pharmacological and pharmacokinetic properties, and safety of DSM265, which supported its advancement to human trials. DSM265 is highly selective towards DHODH of the malaria parasite Plasmodium, efficacious against both blood and liver stages of P. falciparum, and active against drug-resistant parasite isolates. Favorable pharmacokinetic properties of DSM265 are predicted to provide therapeutic concentrations for more than 8 days after a single oral dose in the range of 200–400 mg. DSM265 was well tolerated in repeat dose and cardiovascular safety studies in mice and dogs, was not mutagenic, and was inactive against panels of human enzymes/receptors. The excellent safety profile, blood and liver-stage activity, and predicted long human half-life position DSM265 as a new potential drug combination partner for either single-dose treatment or once weekly chemoprevention. DSM265 has advantages over current treatment options that are dosed daily or are inactive on the parasite liver-stage