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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]

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