SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1.
SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1.
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DOI：
10.1021/acsmedchemlett.5b00319
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发表时间：
2015-12-10
影响因子：
4.2
通讯作者：
Fan E
中科院分区：
文献类型：
--
作者：
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
我们之前发现基于5-氨基吡唑-4-羧酰胺支架的化合物是弓形虫CDPK1的有效和选择性抑制剂。目前的工作，通过构效关系研究，导致发现化合物（34和35）在溶解度、小鼠口服血浆暴露或抑制寄生虫生长功效方面优于起始抑制剂1。化合物34和35在小鼠感染模型中被进一步证明比1更有效，并显著减少脑、脾和腹膜液中弓形虫的数量，以20 mg/kg剂量给药的35可消除腹膜液中的弓形虫。
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.