Selection and optimization of hits from a high-throughput phenotypic screen against Trypanosoma cruzi
| Autor: | Martine Keenan, Eileen Ryan, Susan A. Charman, Jason H. Chaplin, Karen L. White, Eric Chatelain, Gong Chen, Jean-Robert Ioset, Zhisen Wang, Michael J. Abbott, Scott Cornwall, Wayne M. Best, Sarah Keatley, Paul W. Alexander, Thomas W. von Geldern, Hugo Diao, Catherine J. Perez, R.C. Andrew Thompson |
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| Rok vydání: | 2013 |
| Předmět: |
Time Factors
Cell Survival Trypanosoma cruzi Phenotypic screening Administration Oral Computational biology Pharmacology Cell Line Mice Structure-Activity Relationship Parasitic Sensitivity Tests In vivo parasitic diseases Drug Discovery High-Throughput Screening Assays Animals Cytochrome P-450 CYP3A Humans Chagas Disease Selection (genetic algorithm) Cytochrome P-450 CYP3A Inhibitors biology Drug discovery biology.organism_classification Trypanocidal Agents Rats Survival Rate Disease Models Animal Drug development Molecular Medicine |
| Zdroj: | Future Medicinal Chemistry. 5:1733-1752 |
| ISSN: | 1756-8927 1756-8919 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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