Download MendeleyLead 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.
Brand, S., Norcross, N.R., Thompson, S., Harrison, J.R., Smith, V.C., Robinson, D.A., Torrie, L.S., McElroy, S.P., Hallyburton, I., Norval, S., Scullion, P., Stojanovski, L., Simeons, F.R., van Aalten, D., Frearson, J.A., Brenk, R., Fairlamb, A.H., Ferguson, M.A., Wyatt, P.G., Gilbert, I.H., Read, K.D.(2014) J Med Chem 57: 9855-9869
- PubMed: 25412409
- DOI: https://doi.org/10.1021/jm500809c
- Primary Citation of Related Structures:
4UWI, 4UWJ - PubMed Abstract:
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.
Organizational Affiliation:
Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee DD1 5EH, U.K.
