Departments of Chemistry and Global Health, University of Washington, Seattle, Washington 98195, United States.
Departments of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9135, United States.
J Med Chem. 2020 May 14;63(9):4929-4956. doi: 10.1021/acs.jmedchem.0c00311. Epub 2020 Apr 16.
Malaria puts at risk nearly half the world's population and causes high mortality in sub-Saharan Africa, while drug resistance threatens current therapies. The pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (DHODH) is a validated target for malaria treatment based on our finding that triazolopyrimidine DSM265 () showed efficacy in clinical studies. Herein, we describe optimization of a pyrrole-based series identified using a target-based DHODH screen. Compounds with nanomolar potency versus DHODH and parasites were identified with good pharmacological properties. X-ray studies showed that the pyrroles bind an alternative enzyme conformation from leading to improved species selectivity versus mammalian enzymes and equivalent activity on and DHODH. The best lead DSM502 () showed efficacy at similar levels of blood exposure to , although metabolic stability was reduced. Overall, the pyrrole-based DHODH inhibitors provide an attractive alternative scaffold for the development of new antimalarial compounds.
疟疾使世界近一半人口面临风险，并导致撒哈拉以南非洲地区高死亡率，而耐药性则威胁到目前的治疗方法。嘧啶生物合成酶二氢乳清酸脱氢酶（DHODH）是疟疾治疗的一个经过验证的靶点，这是基于我们发现三唑并嘧啶 DSM265（）在临床研究中显示出疗效。在此，我们描述了基于嘧啶的系列化合物的优化，该系列化合物是使用基于靶标的 DHODH 筛选确定的。具有针对 DHODH 和寄生虫的纳摩尔效力的化合物具有良好的药理学性质。X 射线研究表明，吡咯与一种替代酶构象结合，从而提高了对哺乳动物酶的物种选择性，并与 和 DHODH 具有同等的活性。最佳先导化合物 DSM502（）表现出相似的血液暴露水平的疗效，尽管代谢稳定性降低。总体而言，基于吡咯的 DHODH 抑制剂为开发新的抗疟化合物提供了一种有吸引力的替代骨架。
