title: Imidazo[1,2-b]pyridazines: a potent and selective class of cyclin-dependent kinase inhibitors.
abstract: Modification of imidazo[1,2-a]pyridine CDK inhibitors lead to identification of less lipophilic imidazo[1,2-b]pyridazine series of CDK inhibitors. Although several equivalent compounds from these two series have similar structure and show similar CDK activity, the SAR of the two series differs significantly. Protein inhibitor structure determination has confirmed differences in binding mode and given some understanding of these differences in SAR. Potent and selective imidazo[1,2-b]pyridazine inhibitors of CDK2 have been identified, which show >1 microM plasma levels following a 2mg/kg oral dose to mice.
authors.affiliation: Cancer Research, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
authors.forename: Kate F
authors.initials: KF
authors.lastname: Byth
authors.forename: Nicola
authors.initials: N
authors.lastname: Cooper
authors.forename: Janet D
authors.initials: JD
authors.lastname: Culshaw
authors.forename: David W
authors.initials: DW
authors.lastname: Heaton
authors.forename: Sandra E
authors.initials: SE
authors.lastname: Oakes
authors.forename: Claire A
authors.initials: CA
authors.lastname: Minshull
authors.forename: Richard A
authors.initials: RA
authors.lastname: Norman
authors.forename: Richard A
authors.initials: RA
authors.lastname: Pauptit
authors.forename: Julie A
authors.initials: JA
authors.lastname: Tucker
authors.forename: Jason
authors.initials: J
authors.lastname: Breed
authors.forename: Andrew
authors.initials: A
authors.lastname: Pannifer
authors.forename: Siân
authors.initials: S
authors.lastname: Rowsell
authors.forename: Judith J
authors.initials: JJ
authors.lastname: Stanway
authors.forename: Anna L
authors.initials: AL
authors.lastname: Valentine
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Thomas
mesh_terms: D000818:Animals; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000097:blood / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008958:Models, Molecular; D011724:Pyridazines / Q000097:blood / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D011724:Pyridazines; D018844:Cyclin-Dependent Kinases