Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues
Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues
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DOI：
10.1016/j.bmcl.2013.08.010
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发表时间：
2013-11-01
影响因子：
2.7
通讯作者：
Holder, Anthony A.
中科院分区：
文献类型：
--
作者：
Large, Jonathan M.;Osborne, Simon A.;Holder, Anthony A.
恶性疟原虫钙依赖性蛋白激酶1 （PfCDPK1）咪唑吡嗪抑制剂系列的结构多样性和SAR已被探索和扩展。通过降低logd进一步改善关键ADME参数的机会被发现，这是通过用吡唑取代六元（杂）芳香连接剂来实现的。一项简短的SAR研究提供了具有有用的体外活性和ADME谱，对人类激酶组具有良好选择性和提高亲脂配体效率水平的关键示例。因此，这些新的类似物为该系列的进一步发展提供了可靠的额外途径。(C) 2013年作者。Elsevier Ltd.出版。版权所有。
The structural diversity and SAR in a series of imidazopyridazine inhibitors of Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) has been explored and extended. The opportunity to further improve key ADME parameters by means of lowering log D was identified, and this was achieved by replacement of a six-membered (hetero)aromatic linker with a pyrazole. A short SAR study has delivered key examples with useful in vitro activity and ADME profiles, good selectivity against a human kinase panel and improved levels of lipophilic ligand efficiency. These new analogues thus provide a credible additional route to further development of the series. (C) 2013 The Authors. Published by Elsevier Ltd. All rights reserved.