Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)

Bioorg Med Chem Lett. 2013 May 15;23(10):3064-9. doi: 10.1016/j.bmcl.2013.03.017. Epub 2013 Mar 21.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antimalarials / administration & dosage
  • Antimalarials / chemistry
  • Antimalarials / pharmacology*
  • Antimalarials / therapeutic use
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • High-Throughput Screening Assays
  • Malaria / drug therapy*
  • Malaria / parasitology
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Parasitic Sensitivity Tests
  • Plasmodium falciparum / drug effects
  • Plasmodium falciparum / enzymology*
  • Protein Kinase Inhibitors / administration & dosage
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology*
  • Protein Kinase Inhibitors / therapeutic use
  • Protein Kinases / metabolism
  • Protozoan Proteins / antagonists & inhibitors*
  • Protozoan Proteins / metabolism
  • Pyridazines / administration & dosage
  • Pyridazines / chemistry
  • Pyridazines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Antimalarials
  • Protein Kinase Inhibitors
  • Protozoan Proteins
  • Pyridazines
  • Protein Kinases
  • calcium-dependent protein kinase-1, Plasmodium falciparum