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Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei.

ABSTRACT: 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.

SUBMITTER: Cleghorn LA 

PROVIDER: S-EPMC4601051 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei.

Cleghorn Laura A T LA   Albrecht Sébastien S   Stojanovski Laste L   Simeons Frederick R J FR   Norval Suzanne S   Kime Robert R   Collie Iain T IT   De Rycker Manu M   Campbell Lorna L   Hallyburton Irene I   Frearson Julie A JA   Wyatt Paul G PG   Read Kevin D KD   Gilbert Ian H IH  

Journal of medicinal chemistry 20150929 19

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  ...[more]

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