The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing.
The development of a novel series of imidazole pyrimidine amides as cyclin-dependent kinase (CDK) inhibitors is described. Optimisation of inhibitory potency against multiple CDK's (1, 2 and 9) resulted in imidazole pyrimidine amides with potent in vitro anti-proliferative effects against a range of cancer cell lines. Excellent physiochemical properties and large margins against inhibition of CYP isoforms and the hERG ion channel were achieved by modification of lipophilicity and amine basicity. A candidate with disease model activity in human cancer cell line xenografts and with suitable physiochemical and pharmacokinetic profiles for intravenous (i.v.) dosing was selected for further development as AZD5597.
Jones
Clifford D
CD
Cancer and Infection Research, AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TG, UK. cliff.jones@astrazeneca.com
Andrews
David M
DM
Barker
Andrew J
AJ
Blades
Kevin
K
Daunt
Paula
P
East
Simon
S
Geh
Catherine
C
Graham
Mark A
MA
Johnson
Keith M
KM
Loddick
Sarah A
SA
McFarland
Heather M
HM
McGregor
Alexandra
A
Moss
Louise
L
Rudge
David A
DA
Simpson
Peter B
PB
Swain
Michael L
ML
Tam
Kin Y
KY
Tucker
Julie A
JA
Walker
Mike
M
D000577:Amides / Q000737:chemistry*; D045744:Cell Line, Tumor; D002627:Chemistry, Physical / Q000379:methods; D018360:Crystallography, X-Ray; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007262:Infusions, Intravenous; D008956:Models, Chemical; D008968:Molecular Conformation; D009368:Neoplasm Transplantation; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C540146:AZD5597; D000577:Amides; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; C000606913:KCNH2 protein, human; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines