Lead Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series for the Treatment of Malaria

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 (1) 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 Plasmodium DHODH and Plasmodium parasites were
identified with good pharmacological properties. X-ray studies showed
that the pyrroles bind an alternative enzyme conformation from 1 leading to improved species selectivity versus mammalian
enzymes and equivalent activity on Plasmodium falciparum and Plasmodium vivax DHODH. The best
lead DSM502 (37) showed in vivo efficacy
at similar levels of blood exposure to 1, 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（Malaria）威胁全球近半数人口的健康安全，并在撒哈拉以南非洲地区造成极高死亡率；与此同时，耐药性问题正对现有抗疟治疗方案构成严重威胁。嘧啶生物合成酶二氢乳清酸脱氢酶（dihydroorotate dehydrogenase, DHODH）是经过验证的疟疾治疗靶点，这一结论基于我们的研究发现：三唑并嘧啶（triazolopyrimidine）类化合物DSM265（1）在临床研究中展现出明确的抗疟疗效。本文报道了基于靶点的DHODH筛选所发现的吡咯类化合物系列的优化研究工作。研究中成功获得了对疟原虫（Plasmodium）DHODH及疟原虫具有纳摩尔级活性、且具备良好药理学特性的化合物。X射线晶体学研究表明，该类吡咯化合物与化合物1结合的酶构象存在差异，这使其相较于哺乳动物酶的物种选择性得以提升，同时对恶性疟原虫（Plasmodium falciparum）和间日疟原虫（Plasmodium vivax）的DHODH均具有相当的活性。最优先导化合物DSM502（37）的体内抗疟疗效与化合物1相当，血药暴露量也与1相近，但代谢稳定性有所下降。综上，吡咯类DHODH抑制剂为新型抗疟化合物的开发提供了极具潜力的替代骨架。