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. © 2013 Elsevier Ltd. All rights reserved.
Large, J. M., Osborne, S. A., Smiljanic-Hurley, E., Ansell, K. H., Jones, H. M., Taylor, D. L., … Holder, A. A. (2013). Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues. Bioorganic and Medicinal Chemistry Letters, 23(21), 6019–6024. https://doi.org/10.1016/j.bmcl.2013.08.010