Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis
Pharmacokinetics and In Vivo Efficacy of Pyrazolopyrimidine, Pyrrolopyrimidine, and 5-Aminopyrazole-4-Carboxamide Bumped Kinase Inhibitors against Toxoplasmosis
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DOI：
10.1093/infdis/jiy664
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发表时间：
2019-05-01
影响因子：
6.4
通讯作者：
Doggett, J. Stone
中科院分区：
文献类型：
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作者：
Hulverson, Matthew A.;Bruzual, Igor;Doggett, J. Stone
Bumped激酶抑制剂（BKI）已被证明是弓形虫钙依赖性蛋白激酶1的有效抑制剂。基于吡唑并嘧啶和5-氨基吡唑-4-甲酰胺支架的BKI在弓形虫病的急性和慢性实验模型中有效。通过对这两种支架和一种新的吡咯并嘧啶支架的进一步探索，已经鉴定出对急性实验性弓形虫病极其有效的其他化合物。这些BKI的体内功效表明，环丙氧基萘基、环丙氧基喹啉和2-乙氧基喹啉-6-基取代基与跨支架的功效相关。此外，口服给药后的血浆浓度范围很广，这是由于BKI的微小结构变化所致。这些选择的BKI包括抗弓形虫化合物，其对急性实验性弓形虫病有效，并且在人类细胞测定中无毒，当施用用于治疗时对小鼠也无毒。这里描述的BKI是改善抗弓形虫治疗的有希望的晚期线索。
Bumped kinase inhibitors (BKIs) have been shown to be potent inhibitors of Toxoplasma gondii calcium-dependent protein kinase 1. Pyrazolopyrimidine and 5-aminopyrazole-4-carboxamide scaffold-based BKIs are effective in acute and chronic experimental models of toxoplasmosis. Through further exploration of these 2 scaffolds and a new pyrrolopyrimidine scaffold, additional compounds have been identified that are extremely effective against acute experimental toxoplasmosis. The in vivo efficacy of these BKIs demonstrates that the cyclopropyloxynaphthyl, cyclopropyloxyquinoline, and 2-ethoxyquinolin-6-yl substituents are associated with efficacy across scaffolds. In addition, a broad range of plasma concentrations after oral dosing resulted from small structural changes to the BKIs. These select BKIs include anti-Toxoplasma compounds that are effective against acute experimental toxoplasmosis and are not toxic in human cell assays, nor to mice when administered for therapy. The BKIs described here are promising late leads for improving anti-Toxoplasma therapy.