Drugs for Neglected Diseases initiative (DNDi), 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland.
Sandexis Medicinal Chemistry Ltd, Innovation House, Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, U.K.
J Med Chem. 2021 Nov 11;64(21):16159-16176. doi: 10.1021/acs.jmedchem.1c01437. Epub 2021 Oct 28.
Visceral leishmaniasis (VL) is a parasitic disease endemic across multiple regions of the world and is fatal if untreated. Current therapies are unsuitable, and there is an urgent need for safe, short-course, and low-cost oral treatments to combat this neglected disease. The benzoxaborole chemotype has previously delivered clinical candidates for the treatment of other parasitic diseases. Here, we describe the development and optimization of this series, leading to the identification of compounds with potent and antileishmanial activity. The lead compound (DNDI-6148) combines impressive efficacy (>98% reduction in parasite burden) with pharmaceutical properties suitable for onward development and an acceptable safety profile. Detailed mode of action studies confirm that DNDI-6148 acts principally through the inhibition of cleavage and polyadenylation specificity factor (CPSF3) endonuclease. As a result of these studies and its promising profile, DNDI-6148 has been declared a preclinical candidate for the treatment of VL.
内脏利什曼病（VL）是一种寄生虫病，在世界多个地区流行，如果不治疗则会致命。目前的治疗方法并不合适，因此迫切需要安全、短程和低成本的口服治疗方法来对抗这种被忽视的疾病。苯并恶硼烷化学型此前为治疗其他寄生虫病提供了临床候选药物。在这里，我们描述了该系列的开发和优化，从而确定了具有强效和抗利什曼原虫活性的化合物。先导化合物（DNDI-6148）结合了令人印象深刻的疗效（寄生虫负荷减少>98%）和适合进一步开发的药物特性，以及可接受的安全性。详细的作用机制研究证实，DNDI-6148 主要通过抑制切割和多聚腺苷酸化特异性因子（CPSF3）内切酶来发挥作用。由于这些研究及其有前景的特性，DNDI-6148 已被宣布为治疗内脏利什曼病的临床前候选药物。
