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

Jeremy P. Mallari, Fangyi Zhu, Andrew Lemoff, Marcel Kaiser, Min Lu, Reto Brun, R. Kiplin Guy

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


There are currently only four clinical drugs available for treating human African trypanosomiasis (HAT), three of which were developed over 60 years 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 200 mg/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.

Original languageEnglish
Pages (from-to)8302-8309
Number of pages8
JournalBioorganic and Medicinal Chemistry
Issue number23
StatePublished - Dec 1 2010

Bibliographical note

Funding Information:
This work was supported by the American Lebanese Syrian Associated Charities (ALSAC) and St. Jude Children’s Research Hospital (SJCRH) . We acknowledge the contributions of the High Throughput Analytical Chemistry Core at SJCRH. We would like to thank Zachary Mackey and Jim McKerrow for their advice during the efficacy experiments. We would also like to thank Jill Riggs for all of her help and technical assistance.


  • Human African trypanosomiasis
  • Parasite
  • Protease inhibitor
  • TbCatB

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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