Centre for Therapeutics Discovery, MRC Technology, Mill Hill, London NW7 1AD, UK.
Bioorg Med Chem Lett. 2013 Nov 1;23(21):6019-24. doi: 10.1016/j.bmcl.2013.08.010. Epub 2013 Aug 11.
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 logD 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.
已经探索并扩展了一系列抑制恶性疟原虫钙依赖蛋白激酶 1（PfCDPK1）的咪唑并哒嗪抑制剂的结构多样性和 SAR。通过降低 logD，可以进一步改善关键的 ADME 参数，这是通过用吡唑替换六元（杂）芳族连接子来实现的。一项简短的 SAR 研究提供了具有有用的体外活性和 ADME 特征、对人类激酶谱具有良好选择性以及提高亲脂性配体效率的关键实例。这些新类似物因此为进一步开发该系列提供了一条可靠的途径。
