期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 64, 期 9, 页码 6085-6136出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00173
关键词
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资金
- United States National Institutes of Health (NIH) [R01AI103947]
- Medicines for Malaria Venture
- Bill & Melinda Gates Foundation [26296]
- Welch Foundation [I-1257]
- NIH [R01 AI109023, AI093380, AI139179, AI089688]
- Department of Defense [E01 W81XWH1910086]
DHODH has been clinically validated as a target for new antimalarials, and a structure-based computationally driven lead optimization program of DHODH inhibitors has led to the discovery of two promising candidates for potential advancement to preclinical development. These compounds exhibit improved physicochemical properties, potent antimalarial activity in vitro, and good efficacy in Plasmodium falciparum SCID mouse models, showing selectivity for Plasmodium DHODHs versus mammalian enzymes.
Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) 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 in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.
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