The design and synthesis of potent and selective inhibitors of trypanosoma brucei glycogen synthase kinase 3 for the treatment of human African trypanosomiasis

TY - JOUR

T1 - The design and synthesis of potent and selective inhibitors of trypanosoma brucei glycogen synthase kinase 3 for the treatment of human African trypanosomiasis

AU - Urich, Robert

AU - Grimaldi, Raffaella

AU - Luksch, Torsten

AU - Frearson, Julie A.

AU - Brenk, Ruth

AU - Wyatt, Paul G.

PY - 2014/9/25

Y1 - 2014/9/25

N2 - 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 GSK3ß enzyme, have been prepared. These potent kinase inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.

AB - 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 GSK3ß enzyme, have been prepared. These potent kinase inhibitors demonstrated low micromolar levels of inhibition of the Trypanosoma brucei brucei parasite grown in culture.

UR - https://www.scopus.com/pages/publications/84907578173

U2 - 10.1021/jm500239b

DO - 10.1021/jm500239b

M3 - Article

C2 - 25198388

AN - SCOPUS:84907578173

SN - 0022-2623

VL - 57

SP - 7536

EP - 7549

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 18

ER -