Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi.

Abstract:

BACKGROUND:Inhibitors of Trypanosoma cruzi with novel mechanisms of action are urgently required to diversify the current clinical and preclinical pipelines. Increasing the number and diversity of hits available for assessment at the beginning of the discovery process will help to achieve this aim. RESULTS:We report the evaluation of multiple hits generated from a high-throughput screen to identify inhibitors of T. cruzi and from these studies the discovery of two novel series currently in lead optimization. Lead compounds from these series potently and selectively inhibit growth of T. cruzi in vitro and the most advanced compound is orally active in a subchronic mouse model of T. cruzi infection. CONCLUSION:High-throughput screening of novel compound collections has an important role to play in diversifying the trypanosomatid drug discovery portfolio. A new T. cruzi inhibitor series with good drug-like properties and promising in vivo efficacy has been identified through this process.

journal_name

Future Med Chem

authors

Keenan M,Alexander PW,Chaplin JH,Abbott MJ,Diao H,Wang Z,Best WM,Perez CJ,Cornwall SM,Keatley SK,Thompson RC,Charman SA,White KL,Ryan E,Chen G,Ioset JR,von Geldern TW,Chatelain E

doi

10.4155/fmc.13.139

subject

Has Abstract

pub_date

2013-10-01 00:00:00

pages

1733-52

issue

15

eissn

1756-8919

issn

1756-8927

journal_volume

5

pub_type

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