ABSTRACT
To combat drug resistance, new chemical entities are urgently required for use in next generation anti-malarial combinations. We report here the results of a medicinal chemistry programme focused on an imidazopyridine series targeting the Plasmodium falciparum cyclic GMP-dependent protein kinase (PfPKG). The most potent compound (ML10) has an IC50 of 160 pM in a PfPKG kinase assay and inhibits P. falciparum blood stage proliferation in vitro with an EC50 of 2.1 nM. Oral dosing renders blood stage parasitaemia undetectable in vivo using a P. falciparum SCID mouse model. The series targets both merozoite egress and erythrocyte invasion, but crucially, also blocks transmission of mature P. falciparum gametocytes to Anopheles stephensi mosquitoes. A co-crystal structure of PvPKG bound to ML10, reveals intimate molecular contacts that explain the high levels of potency and selectivity we have measured. The properties of this series warrant consideration for further development to produce an antimalarial drug.Protein kinases are promising drug targets for treatment of malaria. Here, starting with a medicinal chemistry approach, Baker et al. generate an imidazopyridine that selectively targets Plasmodium falciparum PKG, inhibits blood stage parasite growth in vitro and in mice and blocks transmission to mosquitoes.
Subject(s)
Cyclic GMP-Dependent Protein Kinases/antagonists & inhibitors , Imidazoles/therapeutic use , Malaria/enzymology , Malaria/transmission , Pyridines/therapeutic use , Animals , Cell Line , Crystallography, X-Ray , Culicidae , Cyclic GMP-Dependent Protein Kinases/chemistry , Cyclic GMP-Dependent Protein Kinases/metabolism , Disease Models, Animal , Female , Humans , Imidazoles/pharmacology , Life Cycle Stages/drug effects , Malaria/drug therapy , Mice, Inbred BALB C , Models, Molecular , Plasmodium chabaudi/drug effects , Plasmodium falciparum/drug effects , Plasmodium falciparum/growth & development , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Pyridines/pharmacology , Treatment OutcomeABSTRACT
A series of benzimidazole CB(2) receptor agonists were prepared and their properties investigated. Optimisation of the three benzimidazole substituents led to the identification of compound 23, a potent CB(2) full agonist (EC(50) 2.7nM) with excellent selectivity over the CB(1) receptor (>3000-fold). Compound 23 demonstrated good CNS penetration in rat. Further optimisation led to the identification of compound 34 with improved selectivity over hERG and excellent CNS penetration in rat.
