Lead Optimization of a Pyrazole Sulfonamide Series of Trypanosoma brucei N-Myristoyltransferase Inhibitors: Identification and Evaluation of CNS Penetrant Compounds as Potential Treatmen

详细信息    查看全文

• 作者：Stephen Brand ; Neil R. Norcross ; Stephen Thompson ; Justin R. Harrison ; Victoria C. Smith ; David A. Robinson ; Leah S. Torrie ; Stuart P. McElroy ; Irene Hallyburton ; Suzanne Norval ; Paul Scullion ; Laste Stojanovski ; Frederick R. C. Simeons ; Daan van Aalten ; Julie A. Frearson ; Ruth Brenk ; Alan H. Fairlamb ; Michael A. J. Ferguson ; Paul G. Wyatt ; Ian H. Gilbert ; Kevin D. Read
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：December 11, 2014
• 年：2014
• 卷：57
• 期：23
• 页码：9855-9869
• 全文大小：752K
• ISSN：1520-4804

文摘

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鈥揵rain 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.