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Bioorg Med Chem Lett. 2013 Nov 1;23(21):6019-24. doi: 10.1016/j.bmcl.2013.08.010. Epub 2013 Aug 11.

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

Author information

  • 1Centre for Therapeutics Discovery, MRC Technology, Mill Hill, London NW7 1AD, UK. Electronic address: jonathan.large@tech.mrc.ac.uk.

Erratum in

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):397.

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 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.

Copyright © 2013 The Authors. Published by Elsevier Ltd.. All rights reserved.

KEYWORDS:

Calcium-dependent protein kinase 1; Imidazopyridazine; Malaria; Plasmodium falciparum; SAR

PMID:
24035097
[PubMed - indexed for MEDLINE]
PMCID:
PMC3809513
Free PMC Article
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