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

Autor:	Cleghorn, Laura A. T., Albrecht, Sébastien, Stojanovski, Laste, Simeons, Frederick R. J., Norval, Suzanne, Kime, Robert, Collie, Iain T., De Rycker, Manu, Campbell, Lorna, Hallyburton, Irene, Frearson, Julie A., Wyatt, Paul G., Read, Kevin D., Gilbert, Ian H.
Jazyk:	angličtina
Rok vydání:	2015
Předmět:	Indoles Trypanosoma brucei brucei Drug Evaluation Preclinical Brain Mice Inbred Strains Stereoisomerism Chemistry Techniques Synthetic Trypanocidal Agents Article Disease Models Animal Structure-Activity Relationship Trypanosomiasis African parasitic diseases Drug Discovery Animals Female
Zdroj:	Journal of Medicinal Chemistry
ISSN:	1520-4804 0022-2623
Popis:	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.
Databáze:	OpenAIRE
Externí odkaz:	https://explore.openaire.eu/search/publication?articleId=pmid________::c46279747bf65cbe17ebc70d12566835 http://europepmc.org/articles/PMC4601051 Zobrazit plný text záznamu