Optimization of purine-nitrile TbcatB inhibitors for use in vivo and evaluation of efficacy in murine models

Mallari, J. P. and Zhu, F. and Lemoff, A. and Kaiser, M. and Lu, M. and Brun, R. and Guy, R. K.. (2010) Optimization of purine-nitrile TbcatB inhibitors for use in vivo and evaluation of efficacy in murine models. Bioorganic & medicinal chemistry : a Tetrahedron publication for the rapid dissemenination of full original research papers and critical reviews on biomolecular chemistry, medicinal chemistry and related disciplines, 18 (23). pp. 8302-8309.

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Official URL: http://edoc.unibas.ch/dok/A5842967

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There are currently only four clinical drugs available for treating human African trypanosomiasis (HAT), three of which were developed over 60years ago. Despite years of effort, there has been relatively little progress towards identifying orally available chemotypes active against the parasite in vivo. Here, we report the lead optimization of a purine-nitrile scaffold that inhibits the essential TbcatB protease and its evaluation in murine models. A lead inhibitor that had potent activity against the trypanosomal protease TbcatB in vitro and cultured parasites ex vivo was optimized by rationally driven medicinal chemistry to an inhibitor that is orally available, penetrates the CNS, has a promising pharmacokinetic profile, and is non-toxic at 200mg/kg in a repeat dosage study. Efficacy models using oral administration of this lead inhibitor showed a significantly increased survival time in Trypanosoma brucei brucei infected mice but little effect on Trypanosoma brucei rhodesiense infected mice
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Medical Parasitology and Infection Biology (MPI) > Parasite Chemotherapy (Mäser)
UniBasel Contributors:Brun, Reto and Kaiser, Marcel
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:08 Dec 2017 13:58
Deposited On:14 Sep 2012 06:46

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