Medicines for Malaria Venture, 1215 Geneva, Switzerland.
Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9135, United States.
J Med Chem. 2021 May 13;64(9):6085-6136. doi: 10.1021/acs.jmedchem.1c00173. Epub 2021 Apr 20.
Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 () suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity against blood and liver schizont stages and show good efficacy in SCID mouse models. They are equally active against and field isolates and are selective for DHODHs versus mammalian enzymes.
二氢乳清酸脱氢酶 (DHODH) 已在临床上被验证为开发新抗疟药物的靶点。三唑并嘧啶类临床候选药物 DSM265()的经验表明，DHODH 抑制剂在预防方面具有很大的潜力，这是流行国家抗疟药物发现组合中未满足的需求，特别是在非洲高传播地区。我们描述了一个基于结构的计算驱动的基于吡咯的 DHODH 抑制剂系列的先导优化计划，该计划导致发现了两个有潜力推进到临床前开发的候选药物。这些化合物在理化性质上优于之前的系列先导化合物，而且它们没有表现出时间依赖性 CYP 抑制作用，这是早期化合物的特征。先导化合物对血期和肝期疟原虫具有很强的抗疟活性，并在 SCID 小鼠模型中显示出良好的疗效。它们对 和 分离株同样有效，并且对 DHODH 具有选择性，而对哺乳动物酶则没有选择性。
