Blank Brian R, Gonciarz Ryan L, Talukder Poulami, Gut Jiri, Legac Jennifer, Rosenthal Philip J, Renslo Adam R
Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94143, United States.
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States.
ACS Infect Dis. 2020 Jul 10;6(7):1827-1835. doi: 10.1021/acsinfecdis.0c00064. Epub 2020 May 18.
The emergence of artemisinin resistance, combined with certain suboptimal properties of ozonide agents arterolane and artefenomel, has necessitated the search for new drug candidates in the endoperoxide class. Our group has focused on trioxolane analogues with substitution patterns not previously explored. Here, we describe the enantioselective synthesis of analogues bearing a -3″ carbamate side chain and find these to be superior, both in vitro and in vivo, to the previously reported amides. We identified multiple analogues that surpass the oral efficacy of arterolane in the model while exhibiting drug-like properties (logD, solubility, metabolic stability) similar or superior to next-generation clinical candidates like E209 and OZ609. While the preclinical assessment of new analogues is still underway, current data suggest the potential of this chemotype as a likely source of future drug candidates from the endoperoxide class.
青蒿素耐药性的出现，再加上过氧化物类药物蒿甲醚和本芴醇的某些欠佳特性，使得有必要在内过氧化物类别中寻找新的候选药物。我们团队专注于具有此前未探索过的取代模式的三氧杂环戊烷类似物。在此，我们描述了带有 -3″ 氨基甲酸酯侧链的类似物的对映选择性合成，并发现这些类似物在体外和体内均优于先前报道的酰胺。我们鉴定出多个类似物，它们在模型中超过了蒿甲醚的口服疗效，同时展现出与下一代临床候选药物如E209和OZ609相似或更优的类药特性（脂水分配系数、溶解度、代谢稳定性）。虽然新类似物的临床前评估仍在进行中，但目前的数据表明这种化学类型有潜力成为内过氧化物类未来候选药物的一个可能来源。
