Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei.
Basic Information
ID: ALA3621104
Journal: J Med Chem
Title: Discovery of Indoline-2-carboxamide Derivatives as a New Class of Brain-Penetrant Inhibitors of Trypanosoma brucei.
Authors: Cleghorn LA, Albrecht S, Stojanovski L, Simeons FR, Norval S, Kime R, Collie IT, De Rycker M, Campbell L, Hallyburton I, Frearson JA, Wyatt PG, Read KD, Gilbert IH.
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.
CiteXplore: 26418485
DOI: 10.1021/acs.jmedchem.5b00596
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