Imidazo[1,2-b]pyridazines: a potent and selective class of cyclin-dependent kinase inhibitors.
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.
Byth
Kate F
KF
Cancer Research, AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK.
Cooper
Nicola
N
Culshaw
Janet D
JD
Heaton
David W
DW
Oakes
Sandra E
SE
Minshull
Claire A
CA
Norman
Richard A
RA
Pauptit
Richard A
RA
Tucker
Julie A
JA
Breed
Jason
J
Pannifer
Andrew
A
Rowsell
Siân
S
Stanway
Judith J
JJ
Valentine
Anna L
AL
Thomas
Andrew P
AP
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*
D004791:Enzyme Inhibitors; D011724:Pyridazines; D018844:Cyclin-Dependent Kinases