title: 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.
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Laura A T
authors.initials: LA
authors.lastname: Cleghorn
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Albrecht
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Laste
authors.initials: L
authors.lastname: Stojanovski
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Frederick R J
authors.initials: FR
authors.lastname: Simeons
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Norval
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Robert
authors.initials: R
authors.lastname: Kime
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Iain T
authors.initials: IT
authors.lastname: Collie
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Manu
authors.initials: M
authors.lastname: De Rycker
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Lorna
authors.initials: L
authors.lastname: Campbell
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Irene
authors.initials: I
authors.lastname: Hallyburton
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Frearson
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Wyatt
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Kevin D
authors.initials: KD
authors.lastname: Read
authors.affiliation: Drug Discovery Unit, Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee , Sir James Black Centre, Dundee, DD1 5EH, U.K.
authors.forename: Ian H
authors.initials: IH
authors.lastname: Gilbert
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects*; D060326:Chemistry Techniques, Synthetic; D004195:Disease Models, Animal; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D007211:Indoles / Q000737:chemistry; D008815:Mice, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014344:Trypanocidal Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D014346:Trypanosoma brucei brucei / Q000187:drug effects* / Q000254:growth & development; D014353:Trypanosomiasis, African / Q000188:drug therapy* / Q000469:parasitology
chemical_list: D007211:Indoles; D014344:Trypanocidal Agents; C057812:indoline