title: The design and synthesis of potent and selective inhibitors of Trypanosoma brucei glycogen synthase kinase 3 for the treatment of human african trypanosomiasis.
abstract: Glycogen synthase kinase 3 (GSK3) is a genetically validated drug target for human African trypanosomiasis (HAT), also called African sleeping sickness. We report the synthesis and biological evaluation of aminopyrazole derivatives as Trypanosoma brucei GSK3 short inhibitors. Low nanomolar inhibitors, which had high selectivity over the off-target human CDK2 and good selectivity over human GSK3β enzyme, have been prepared. These potent kinase inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.
authors.affiliation: Drug Discovery Unit, College of Life Sciences, University of Dundee , Sir James Black Centre, Dow Street, Dundee DD1 5EH, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Urich
authors.forename: Raffaella
authors.initials: R
authors.lastname: Grimaldi
authors.forename: Torsten
authors.initials: T
authors.lastname: Luksch
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001665:Binding Sites; D060326:Chemistry Techniques, Synthetic; D051357:Cyclin-Dependent Kinase 2 / Q000737:chemistry / Q000378:metabolism; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors*; D006801:Humans; D008958:Models, Molecular; D011487:Protein Conformation; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D013379:Substrate Specificity; D014353:Trypanosomiasis, African / Q000188:drug therapy*
chemical_list: D004791:Enzyme Inhibitors; D011720:Pyrazoles; C031280:pyrazole; D000255:Adenosine Triphosphate; D051357:Cyclin-Dependent Kinase 2; D038362:Glycogen Synthase Kinase 3