title: Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues.
abstract: The structural diversity and SAR in a series of imidazopyridazine inhibitors of Plasmodium falciparum calcium dependent protein kinase 1 (PfCDPK1) has been explored and extended. The opportunity to further improve key ADME parameters by means of lowering logD was identified, and this was achieved by replacement of a six-membered (hetero)aromatic linker with a pyrazole. A short SAR study has delivered key examples with useful in vitro activity and ADME profiles, good selectivity against a human kinase panel and improved levels of lipophilic ligand efficiency. These new analogues thus provide a credible additional route to further development of the series.
authors.affiliation: Centre for Therapeutics Discovery, MRC Technology, Mill Hill, London NW7 1AD, UK. Electronic address: jonathan.large@tech.mrc.ac.uk.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Large
authors.forename: Simon A
authors.initials: SA
authors.lastname: Osborne
authors.forename: Ela
authors.initials: E
authors.lastname: Smiljanic-Hurley
authors.forename: Keith H
authors.initials: KH
authors.lastname: Ansell
authors.forename: Hayley M
authors.initials: HM
authors.lastname: Jones
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: D000962:Antimalarials / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D010963:Plasmodium falciparum / Q000187:drug effects / Q000201:enzymology*; D011494:Protein Kinases / Q000378:metabolism; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011724:Pyridazines / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000962:Antimalarials; D015800:Protozoan Proteins; D011724:Pyridazines; D011494:Protein Kinases; C531238:calcium-dependent protein kinase-1, Plasmodium falciparum
keywords: Calcium-dependent protein kinase 1; Imidazopyridazine; Malaria; Plasmodium falciparum; SAR
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