2. Academic Validation
  3. Lead 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

Lead 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

  • J Med Chem. 2014 Dec 11;57(23):9855-69. doi: 10.1021/jm500809c.
Stephen Brand 1,  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
Affiliations

Affiliation

  • 1 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.
PMID: 25412409 DOI: 10.1021/jm500809c
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.

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