Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues
- Large, Jonathan M.
- Osborne, Simon A.
- Smiljanic-Hurley, Ela
- Ansell, Keith H.
- Jones, Hayley M.
- Taylor, Debra L.
- Clough, Barbara
- Green, Judith L.
- Holder, Anthony A.
Publication date
November 2013
DOI Publisher
The Authors. Published by Elsevier Ltd.Abstract
AbstractThe 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
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