Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues
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- 作者：Jonathan M. Large ; Simon A. Osborne ; Ela Smiljanic-Hurley ; Keith H. Ansell ; Hayley M. Jones ; Debra L. Taylor ; Barbara Clough ; Judith L. Green ; Anthony A. Holder
- 关键词：Plasmodium falciparum ; Calcium-dependent protein kinase 1 ; Malaria ; Imidazopyridazine ; SAR
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2013
- 出版时间：1 November, 2013
- 年：2013
- 卷：23
- 期：21
- 页码：6019-6024
- 全文大小：2825 K
文摘
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.