The Development Process for Discovery and Clinical Advancement of Modern Antimalarials

被引：64

作者：

Ashton, Trent D. ^{[1
,2
]}

Devine, Shane M. ^{[3
]}

Mohrle, Jorg J. ^{[4
]}

Laleu, Benoit ^{[4
]}

Burrows, Jeremy N. ^{[4
]}

Charman, Susan A. ^{[3
]}

Creek, Darren J. ^{[3
]}

Sleebs, Brad E. ^{[1
,2
]}

机构：

[1] Walter & Eliza Hall Inst Med Res, Parkville, Vic 3052, Australia

[2] Univ Melbourne, Dept Med Biol, Parkville, Vic 3052, Australia

[3] Monash Univ, Monash Inst Pharmaceut Sci, 381 Royal Parade, Parkville, Vic 3052, Australia

[4] ICC, Med Malaria Venture, Route Prebois 20, CH-1215 Geneva, Switzerland

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2019年 / 62卷 / 23期

基金：

英国医学研究理事会; 澳大利亚国家健康与医学研究理事会;

关键词：

FALCIPARUM DIHYDROOROTATE DEHYDROGENASE; UNCOMPLICATED PLASMODIUM-FALCIPARUM; MALEATE-PIPERAQUINE PHOSPHATE; ORIENTED SYNTHESIS YIELDS; CATION ATPASE PFATP4; SINGLE-DOSE CURE; DOUBLE-BLIND; ARTEMISININ RESISTANCE; KAE609; CIPARGAMIN; LEAD OPTIMIZATION;

D O I：

10.1021/acs.jmedchem.9b00761

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Malaria is a devastating disease caused by Plasmodium parasites, resulting in approximately 435000 deaths in 2018. The impact of malaria is compounded by the emergence of widespread resistance to current antimalarial therapies. Recently, a new strategy was initiated to screen small molecule collections against the Plasmodium parasite enabling the identification of new antimalarial chemotypes with novel modes of action. This initiative ushered in the modern era of antimalarial drug development, and as a result, numerous lead candidates are advancing toward or are currently in human clinical trials. In this Perspective, we describe the development pathway of four of the most clinically advanced modern antimalarials, KAE609, KAF156, DSM265, and MMV048. Additionally, the mechanism of action and life-cycle stage specificity of the four antimalarials is discussed in relation to aligning with global strategies to treat and eliminate malaria. This perspective serves as a guide to the expectations of modern antimalarial drug development.

引用

页码：10526 / 10562

页数：37

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