Discovery of indoline-2-carboxamide derivatives as a new class of brain-penetrant inhibitors of Trypanosoma brucei

Laura A. T. Cleghorn, Sébastien Albrecht, Laste Stojanovski, Frederick R. J. Simeons, Suzanne Norval, Robert Kime, Iain T. Collie, Manu De Rycker, Lorna Campbell, Irene Hallyburton, Julie A. Frearson, Paul G. Wyatt, Kevin D. Read, Ian H. Gilbert (Lead / Corresponding author)

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)7695-7706
Number of pages12
JournalJournal of Medicinal Chemistry
Volume58
Issue number19
DOIs
Publication statusPublished - 8 Oct 2015

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African Trypanosomiasis
Trypanosoma brucei brucei
Brain
Peptide Hydrolases
Central Nervous System
Pharmacokinetics
indoline

Cite this

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. / Discovery of indoline-2-carboxamide derivatives as a new class of brain-penetrant inhibitors of Trypanosoma brucei. In: Journal of Medicinal Chemistry. 2015 ; Vol. 58, No. 19. pp. 7695-7706.
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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.; 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. (Lead / Corresponding author).

In: Journal of Medicinal Chemistry, Vol. 58, No. 19, 08.10.2015, p. 7695-7706.

Research output: Contribution to journalArticle

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