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

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Chapman, Timothy M. ; Osborne, Simon A. ; Bouloc, Nathalie ; Large, Jonathan M. ; Wallace, Claire ; Birchall, Kristian ; Ansell, Keith H. ; Jones, Hayley M. ; Taylor, Debra ; Clough, Barbara ; Green, Judith L. ; Holder, Anthony A. (2013)
  • Publisher: PERGAMON-ELSEVIER SCIENCE LTD
  • Journal: BIOORGANIC & MEDICINAL CHEMISTRY LETTERS (issn: 0960-894X, vol: 23, pp: 3,064-3,069)
  • Related identifiers: doi: 10.1016/j.bmcl.2013.03.017, pmc: PMC3898741
  • Subject: Molecular Biology | SAR | Pharmaceutical Science | Malaria | Article | Drug Discovery | Organic Chemistry | Plasmodium falciparum | Biochemistry | Molecular Medicine | Imidazopyridazine | Clinical Biochemistry | Calcium-dependent protein kinase 1
    mesheuropmc: parasitic diseases

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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