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

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• 作者：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 Hostos ; Nina Isoherranen ; Dustin J. Maly ; Marilyn Parsons ; J. Stone Doggett ; Wesley C. Van Voorhis ; Erkang Fan
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：December 10, 2015
• 年：2015
• 卷：6
• 期：12
• 页码：1184-1189
• 全文大小：386K
• ISSN：1948-5875

文摘

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鈥揳ctivity 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.