Abstract
Trypanosoma bruceiN-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.
Highlights
Human African trypanosomiasis (HAT) is caused by two subspecies of the protozoan parasite Trypanosoma brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, transmitted by the bite of an infected tetse fly.[1,2] The disease is fatal unless treated
We report the systematic optimization of both the blood−brain barrier penetration and selectivity of 1, which has led to the discovery of central nervous system (CNS) penetrant T. brucei NMT (TbNMT) inhibitors suitable for progression into in vivo proof-of-concept studies in mice for the second stage of HAT
1 has relatively poor/no selectivity at the enzyme level compared to the two human orthologues HsNMT1 and HsNMT2 (IC50 = 0.003 μM), this did not translate to low selectivity at the cellular level
Summary
Human African trypanosomiasis (HAT) is caused by two subspecies of the protozoan parasite Trypanosoma brucei, Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense, transmitted by the bite of an infected tetse fly.[1,2] The disease is fatal unless treated. It has two stages: an initial (hemolymphatic) peripheral infection during which the parasites are found in the bloodstream and gives rise to nonspecific symptoms, and a second stage during which the parasites enter the central nervous system (CNS), giving rise to the classic symptoms of HAT, eventually leading to coma and death. NMT has been investigated as a potential target for the treatment of other parasitic diseases including malaria,[11] leishmaniasis,[12] and Chagas disease.[13]
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