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

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. GilbertKevin D. Read

Research output: Contribution to journalArticle

32 Citations (Scopus)
91 Downloads (Pure)

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.

Original languageEnglish
Pages (from-to)9855-9869
Number of pages15
JournalJournal of Medicinal Chemistry
Volume57
Issue number23
Early online date20 Nov 2014
DOIs
Publication statusPublished - 11 Dec 2014

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

  • Projects

    Profiles

    No photo of Kevin Read

    Read, Kevin

    Person: Academic

    Cite this