biostudies-literatureBrand SMedical Research CouncilWellcome Trust9855-69https://www.ebi.ac.uk/biostudies/studies/S-EPMC4269550biostudies-literatureUnknown57(23)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 sulfonaJournal of medicinal chemistryLead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis.PMC4269550079838WT077705MR/M004139/1092340WT083481087590G0900138101842101842/Z/13/ZWT085622Smith VCMcElroy SPBrenk RSimeons FRNorval STorrie LSScullion PFrearson JAWyatt PGThompson SFairlamb AHBrand SRobinson DAGilbert IHNorcross NRHarrison JRHallyburton IFerguson MAvan Aalten DRead KDStojanovski LfalseLead optimization of a pyrazole sulfonamide series of Trypanosoma brucei N-myristoyltransferase inhibitors: identification and evaluation of CNS penetrant compounds as potential treatments for stage 2 human African trypanosomiasis.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 sulfona2014-01-01T00:00:00Z2014 Dec2026-05-02T05:29:21.088Z2019-03-27T01:41:57ZS-EPMC42695502541240910.1021/jm500809c