Klope Matthew T, Tapia Cardona Juan A, Chen Jun, Gonciarz Ryan L, Cheng Ke, Jaishankar Priyadarshini, Kim Julie, Legac Jenny, Rosenthal Philip J, Renslo Adam R
Department of Pharmaceutical Chemistry, University of California, San Francisco, 600 16th Street, San Francisco, California 94158, United States.
Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California 94143, United States.
ACS Med Chem Lett. 2024 Sep 5;15(10):1764-1770. doi: 10.1021/acsmedchemlett.4c00365. eCollection 2024 Oct 10.
The recent withdrawal of artefenomel from clinical development leaves no endoperoxide-class agents in the antimalarial pipeline. Synthetic endoperoxides with a desymmetrized structure have demonstrated promising physiochemical and properties. Here we expand on our initial investigation of -3″ carbamate substitution with a diverse array of amine-, alcohol-, and sulfinyl-terminated analogues prepared in () and () configurations. In general, this chemotype combines low-nM antiplasmodial activity with excellent aqueous solubility but widely varying human liver microsome (HLM) stability. We evaluated 20 novel analogues in the mouse malaria model, identifying new analogues such as RLA-4767 () and RLA-5489 (), with HLM stability and pharmacokinetic profiles superior to analogues from our initial report (e.g., RLA-4776, ). These new leads approach or equal the efficacy of artefenomel after two daily oral doses of 10 mg/kg, thus revealing a promising chemotype with the potential to deliver development candidates.
阿替非诺近期退出临床开发，使得抗疟药物研发进程中没有了内过氧化物类药物。具有不对称结构的合成内过氧化物已展现出良好的物理化学性质。在此，我们拓展了对-3″氨基甲酸酯取代的初步研究，制备了一系列具有不同胺基、醇基和亚磺酰基端基的类似物，其构型为（）和（）。总体而言，这种化学类型兼具低纳摩尔级的抗疟活性和出色的水溶性，但在人肝微粒体（HLM）中的稳定性差异很大。我们在小鼠疟疾模型中评估了20种新型类似物，鉴定出了如RLA-4767（）和RLA-5489（）等新类似物，它们在HLM中的稳定性和药代动力学特征优于我们初始报告中的类似物（如RLA-4776，）。这些新先导化合物在每日口服两次、剂量为10 mg/kg的情况下，疗效接近或等同于阿替非诺，从而揭示了一种有潜力提供候选开发药物的、前景广阔的化学类型。
