title: 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.
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology, Mill Hill, London NW7 1AD, UK. tim.chapman@tech.mrc.ac.uk
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Chapman
authors.forename: Simon A
authors.initials: SA
authors.lastname: Osborne
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bouloc
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Large
authors.forename: Claire
authors.initials: C
authors.lastname: Wallace
authors.forename: Kristian
authors.initials: K
authors.lastname: Birchall
authors.forename: Keith H
authors.initials: KH
authors.lastname: Ansell
authors.forename: Hayley M
authors.initials: HM
authors.lastname: Jones
authors.forename: Debra
authors.initials: D
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 / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D057166:High-Throughput Screening Assays; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D011494:Protein Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000008:administration & dosage / Q000737:chemistry / 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