There is an urgent need for new,
brain penetrant small molecules
that target the central nervous system second stage of human African
trypanosomiasis (HAT). We report that a series of novel indoline-2-carboxamides
have been identified as inhibitors of Trypanosoma brucei from screening of a focused protease library against Trypanosoma brucei brucei in culture. We describe
the optimization and characterization of this series. Potent antiproliferative
activity was observed. The series demonstrated excellent pharmacokinetic
properties, full cures in a stage 1 mouse model of HAT, and a partial
cure in a stage 2 mouse model of HAT. Lack of tolerability prevented
delivery of a fully curative regimen in the stage 2 mouse model and
thus further progress of this series