Abstract
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.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antimalarials / administration & dosage
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Antimalarials / chemistry
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Antimalarials / pharmacology*
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Antimalarials / therapeutic use
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Disease Models, Animal
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Dose-Response Relationship, Drug
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High-Throughput Screening Assays
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Malaria / drug therapy*
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Malaria / parasitology
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Mice
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Models, Molecular
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Molecular Structure
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Parasitic Sensitivity Tests
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Plasmodium falciparum / drug effects
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Plasmodium falciparum / enzymology*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / chemistry
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Protein Kinases / metabolism
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Protozoan Proteins / antagonists & inhibitors*
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Protozoan Proteins / metabolism
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Pyridazines / administration & dosage
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Pyridazines / chemistry
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Pyridazines / pharmacology*
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Structure-Activity Relationship
Substances
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Antimalarials
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Protein Kinase Inhibitors
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Protozoan Proteins
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Pyridazines
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Protein Kinases
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calcium-dependent protein kinase-1, Plasmodium falciparum