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ACS Med Chem Lett. 2015 Oct 22;6(12):1184-1189. eCollection 2015 Dec 10.

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

Author information

1
Department of Biochemistry, University of Washington , Seattle, Washington 98195, United States.
2
Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington , Seattle, Washington 98109, United States.
3
Department of Chemistry, University of Washington , Seattle, Washington 98195, United States.
4
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States.
5
Portland VA Medical Center , Portland, Oregon 97239, United States.
6
AbbVie , N. Chicago, Illinois 60064, United States.
7
PATH , San Francisco, California 94102, United States.
8
Department of Pharmaceutics, University of Washington , Seattle, Washington 98195, United States.
9
Center for Infectious Disease Research (formerly Seattle Biomedical Research Institute), Seattle, Washington 98109, United States ; Department of Global Health, University of Washington , Seattle, Washington 98195, United States.
10
Department of Medicine, Division of Allergy and Infectious Diseases, and the Center for Emerging and Re-emerging Infectious Diseases (CERID), University of Washington , Seattle, Washington 98109, United States ; Department of Global Health, University of Washington , Seattle, Washington 98195, United States.

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.

KEYWORDS:

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

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