Optimisation of the Anti-Trypanosoma brucei Activity of the Opioid Agonist U50488

Victoria C. Smith, Laura A. T. Cleghorn, Andrew Woodland, Daniel Spinks, Irene Hallyburton, Iain T. Collie, N. Yi Mok, Suzanne Norval, Ruth Brenk, Alan H. Fairlamb, Julie A. Frearson, Kevin D. Read, Ian H. Gilbert, Paul G. Wyatt

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    Abstract

    Screening of the Sigma-Aldrich Library of Pharmacologically Active Compounds (LOPAC) against cultured Trypanosoma brucei, the causative agent of African sleeping sickness, resulted in the identification of a number of compounds with selective antiproliferative activity over mammalian cells. These included (+)-(1R,2R)-U50488, a weak opioid agonist with an EC50 value of 59 nm as determined in our T. brucei in vitro assay reported previously. This paper describes the modification of key structural elements of U50488 to investigate structure-activity relationships (SAR) and to optimise the antiproliferative activity and pharmacokinetic properties of this compound.

    Original languageEnglish
    Pages (from-to)1832-1840
    Number of pages9
    JournalChemMedChem
    Volume6
    Issue number10
    DOIs
    Publication statusPublished - 4 Oct 2011

    Keywords

    • antiprotozoal agents
    • human African trypanosomiasis
    • medicinal chemistry
    • U50488
    • HUMAN AFRICAN TRYPANOSOMIASIS
    • DERIVATIVES
    • DISEASES

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