Optimization of an imidazopyridazine series of inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1).
Optimization of an imidazopyridazine series of inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1).
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DOI：
10.1021/jm500342d
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发表时间：
2014-04-24
影响因子：
7.3
通讯作者：
Holder AA
中科院分区：
文献类型：
--
作者：
Chapman TM;Osborne SA;Wallace C;Birchall K;Bouloc N;Jones HM;Ansell KH;Taylor DL;Clough B;Green JL;Holder AA
使用恶性疟原虫钙依赖性蛋白激酶 1 (PfCDPK1) 同源模型的结构引导设计方法被用来提高一系列咪唑并哒嗪抑制剂作为潜在抗疟药物的效力。这产生了高亲和力化合物，其 PfCDPK1 酶 IC50 值小于 10 nM，并且在体外 P。恶性疟原虫抗寄生虫 EC50 值低至 12 nM，尽管这些化合物不具有合适的 ADME 特性，无法在小鼠模型中显示体内功效。旨在解决 ADME 问题（特别是渗透性）的结构修改最初伴随着抗寄生虫效力的损失，但进一步优化可以实现化合物分布的良好平衡。在小鼠模型中进行体内抗疟疾功效测试后，相对于其体外活性，化合物暴露水平较高，而所产生的适度功效引发了人们对通过靶向 PfCDPK1 可实现的效果水平的疑问。
A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitroP. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.
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