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

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.

SUBMITTER: Chapman TM

PROVIDER: S-EPMC3898741 | biostudies-other | 2013 May

REPOSITORIES: biostudies-other

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

Chapman Timothy M TM Osborne Simon A SA Bouloc Nathalie N Large Jonathan M JM Wallace Claire C Birchall Kristian K Ansell Keith H KH Jones Hayley M HM Taylor Debra D Clough Barbara B Green Judith L JL Holder Anthony A AA

Bioorganic & medicinal chemistry letters 20130321 10

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 ...[more]

PMID: 23570789

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