Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)
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Timothy M Chapman Simon A Osborne Nathalie Bouloc Jonathan M Large Claire Wallace Kristian Birchall Keith H Ansell Hayley M Jones Debra Taylor Barbara Clough Judith Green Anthony HolderAbstract
A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria.
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Volume 23
Issue number 10
Pages 3064-3069
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Publisher website (DOI) 10.1016/j.bmcl.2013.03.017
Europe PubMed Central 23570789
Pubmed 23570789
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