期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 57, 期 23, 页码 9855-9869出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm500809c
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资金
- Wellcome Trust [WT077705, WT083481, WT085622]
- Medical Research Council [G0900138, MR/M004139/1] Funding Source: researchfish
- MRC [G0900138, MR/M004139/1] Funding Source: UKRI
Trypanosoma brucei N-myristoyltransferase (TbNMT) is an attractive therapeutic target for the treatment of human African trypanosomiasis (HAT). From previous studies, we identified pyrazole sulfonamide, DDD85646 (1), a potent inhibitor of TbNMT. Although this compound represents an excellent lead, poor central nervous system (CNS) exposure restricts its use to the hemolymphatic form (stage 1) of the disease. With a clear clinical need for new drug treatments for HAT that address both the hemolymphatic and CNS stages of the disease, a chemistry campaign was initiated to address the shortfalls of this series. This paper describes modifications to the pyrazole sulfonamides which markedly improved blood-brain barrier permeability, achieved by reducing polar surface area and capping the sulfonamide. Moreover, replacing the core aromatic with a flexible linker significantly improved selectivity. This led to the discovery of DDD100097 (40) which demonstrated partial efficacy in a stage 2 (CNS) mouse model of HAT.
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