Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1)
Chapman, Timothy M.
Osborne, Simon A.
Large, Jonathan M.
Ansell, Keith H.
Jones, Hayley M.
Green, Judith L.
Holder, Anthony A.
- Publisher: PERGAMON-ELSEVIER SCIENCE LTD
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
(issn: 0960-894X, vol:
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.