SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1

Wenlin Huang, Kayode K. Ojo, Zhongsheng Zhang, Kasey Rivas, Rama Subba Rao Vidadala, Suzanne Scheele, Amy E. Derocher, Ryan Choi, Matthew A. Hulverson, Lynn K. Barrett, Igor Bruzual, Latha Kallur Siddaramaiah, Keshia M. Kerchner, Matthew D. Kurnick, Gail M. Freiberg, Dale Kempf, Wim G J Hol, Ethan A. Merritt, Georg Neckermann, Eugenio L. De HostosNina Isoherranen, Dustin J. Maly, Marilyn Parsons, Joseph Doggett, Wesley C. Van Voorhis, Erkang Fan

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from T. gondii. The current work, through structure-activity relationship studies, led to the discovery of compounds (34 and 35) with improved characteristics over the starting inhibitor 1 in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds 34 and 35 were further demonstrated to be more effective than 1 in a mouse infection model and markedly reduced the amount of T. gondii in the brain, spleen, and peritoneal fluid, and 35 given at 20 mg/kg eliminated T. gondii from the peritoneal fluid.

Original languageEnglish (US)
Pages (from-to)1184-1189
Number of pages6
JournalACS Medicinal Chemistry Letters
Volume6
Issue number12
DOIs
StatePublished - Dec 10 2015
Externally publishedYes

Keywords

  • calcium-dependent protein kinase-1
  • enzyme inhibitor
  • structure-activity relationship studies
  • Toxoplasma gondii

ASJC Scopus subject areas

  • Organic Chemistry
  • Drug Discovery
  • Biochemistry

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  • Cite this

    Huang, W., Ojo, K. K., Zhang, Z., Rivas, K., Vidadala, R. S. R., Scheele, S., Derocher, A. E., Choi, R., Hulverson, M. A., Barrett, L. K., Bruzual, I., Siddaramaiah, L. K., Kerchner, K. M., Kurnick, M. D., Freiberg, G. M., Kempf, D., Hol, W. G. J., Merritt, E. A., Neckermann, G., ... Fan, E. (2015). SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1. ACS Medicinal Chemistry Letters, 6(12), 1184-1189. https://doi.org/10.1021/acsmedchemlett.5b00319