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Elsevier, Bioorganic and Medicinal Chemistry Letters, 21(23), p. 6019-6024, 2013

DOI: 10.1016/j.bmcl.2013.08.010

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Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues☆

Journal article published in 2013 by 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 ORCID
This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

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.