Anacor Pharmaceuticals, Inc. , 1020 E. Meadow Circle, Palo Alto, California 94303, United States.
Department of Medicine, University of California, San Francisco , Box 0811, San Francisco, California 94143, United States.
J Med Chem. 2017 Jul 13;60(13):5889-5908. doi: 10.1021/acs.jmedchem.7b00621. Epub 2017 Jun 29.
Carboxamide pyrazinyloxy benzoxaboroles were investigated with the goal to identify a molecule with satisfactory antimalarial activity, physicochemical properties, pharmacokinetic profile, in vivo efficacy, and safety profile. This optimization effort discovered 46, which met our target candidate profile. Compound 46 had excellent activity against cultured Plasmodium falciparum, and in vivo against P. falciparum and P. berghei in infected mice. It exhibited good PK properties in mice, rats, and dogs. It was highly active against the other 11 P. falciparum strains, which are mostly resistant to chloroquine and pyrimethamine. The rapid parasite in vitro reduction and in vivo parasite clearance profile of 46 were similar to those of artemisinin and chloroquine, two rapid-acting antimalarials. It was nongenotoxic in an Ames assay, an in vitro micronucleus assay, and an in vivo rat micronucleus assay when dosed orally up to 2000 mg/kg. The combined properties of this novel benzoxaborole support its progression to preclinical development.
我们研究了羧酰胺吡嗪氧基苯并硼杂环戊烷，旨在寻找一种具有满意抗疟活性、理化性质、药代动力学特征、体内疗效和安全性特征的分子。这项优化工作发现了 46，它符合我们的候选药物标准。化合物 46 对培养的疟原虫 falciparum 具有优异的活性，并且在感染小鼠的体内对疟原虫 falciparum 和疟原虫 berghei 具有活性。它在小鼠、大鼠和狗中表现出良好的 PK 特性。它对其他 11 株疟原虫 falciparum 也具有高度活性，这些疟原虫对氯喹和乙胺嘧啶大多具有耐药性。46 的体外寄生虫快速减少和体内寄生虫清除特征与青蒿素和氯喹相似，这两种药物都是快速作用的抗疟药。当以 2000mg/kg 的剂量口服时，它在 Ames 试验、体外微核试验和体内大鼠微核试验中均无遗传毒性。这种新型苯并硼杂环戊烷的综合特性支持其进入临床前开发阶段。
