title: Optimization of an imidazopyridazine series of inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1).
abstract: A structure-guided design approach using a homology model of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was used to improve the potency of a series of imidazopyridazine inhibitors as potential antimalarial agents. This resulted in high affinity compounds with PfCDPK1 enzyme IC50 values less than 10 nM and in vitro P. falciparum antiparasite EC50 values down to 12 nM, although these compounds did not have suitable ADME properties to show in vivo efficacy in a mouse model. Structural modifications designed to address the ADME issues, in particular permeability, were initially accompanied by losses in antiparasite potency, but further optimization allowed a good balance in the compound profile to be achieved. Upon testing in vivo in a murine model of efficacy against malaria, high levels of compound exposure relative to their in vitro activities were achieved, and the modest efficacy that resulted raises questions about the level of effect that is achievable through the targeting of PfCDPK1.
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology , 1-3 Burtonhole Lane, Mill Hill, London NW7 1AD, U.K.
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Chapman
authors.forename: Simon A
authors.initials: SA
authors.lastname: Osborne
authors.forename: Claire
authors.initials: C
authors.lastname: Wallace
authors.forename: Kristian
authors.initials: K
authors.lastname: Birchall
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bouloc
authors.forename: Hayley M
authors.initials: HM
authors.lastname: Jones
authors.forename: Keith H
authors.initials: KH
authors.lastname: Ansell
authors.forename: Debra L
authors.initials: DL
authors.lastname: Taylor
authors.forename: Barbara
authors.initials: B
authors.lastname: Clough
authors.forename: Judith L
authors.initials: JL
authors.lastname: Green
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Holder
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011494:Protein Kinases / Q000737:chemistry; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D047428:Protein Kinase Inhibitors; D015800:Protozoan Proteins; D011724:Pyridazines; D011494:Protein Kinases; C531238:calcium-dependent protein kinase-1, Plasmodium falciparum