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Optimisation of the Anti‐ Trypanosoma brucei Activity of the Opioid Agonist U50488
Author(s) -
Smith Victoria C.,
Cleghorn Laura A. T.,
Woodland Andrew,
Spinks Daniel,
Hallyburton Irene,
Collie Iain T.,
Yi Mok N.,
Norval Suzanne,
Brenk Ruth,
Fairlamb Alan H.,
Frearson Julie A.,
Read Kevin D.,
Gilbert Ian H.,
Wyatt Paul G.
Publication year - 2011
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201100278
Subject(s) - trypanosoma brucei , agonist , pharmacology , in vitro , opioid , chemistry , biology , biochemistry , receptor , gene
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 (+)‐(1 R ,2 R )‐U50488, a weak opioid agonist with an EC 50 value of 59 n M 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.