SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1.
Basic Information
ID: ALA3769379
Journal: ACS Med Chem Lett
Title: SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1.
Authors: Huang W, Ojo KK, Zhang Z, Rivas K, Vidadala RS, Scheele S, DeRocher AE, Choi R, Hulverson MA, Barrett LK, Bruzual I, Siddaramaiah LK, Kerchner KM, Kurnick MD, Freiberg GM, Kempf D, Hol WG, Merritt EA, Neckermann G, de Hostos EL, Isoherranen N, Maly DJ, Parsons M, Doggett JS, Van Voorhis WC, Fan E.
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.
CiteXplore: 26693272
DOI: 10.1021/acsmedchemlett.5b00319
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