The discovery of AZD5597, a potent imidazole pyrimidine amide CDK inhibitor suitable for intravenous dosing.

Abstract	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.
Authors	Clifford D Jones, David M Andrews, Andrew J Barker, Kevin Blades, Paula Daunt, Simon East, Catherine Geh, Mark A Graham, Keith M Johnson, Sarah A Loddick, Heather M McFarland, Alexandra McGregor, Louise Moss, David A Rudge, Peter B Simpson, Michael L Swain, Kin Y Tam, Julie A Tucker, Mike Walker
Journal	Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 18 Issue 24 Pg. 6369-73 (Dec 15 2008) ISSN: 1464-3405 [Electronic] England
PMID	18996007 (Publication Type: Journal Article)
Chemical References	AZD5597 Amides Cyclin-Dependent Kinase Inhibitor Proteins ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels Imidazoles KCNH2 protein, human Protein Isoforms Protein Kinase Inhibitors Pyrimidines
Topics	Amides (chemistry) Cell Line, Tumor Chemistry, Physical (methods) Crystallography, X-Ray Cyclin-Dependent Kinase Inhibitor Proteins (chemistry, pharmacology) Drug Design ERG1 Potassium Channel Ether-A-Go-Go Potassium Channels (metabolism) Humans Imidazoles (chemical synthesis, pharmacology) Infusions, Intravenous Models, Chemical Molecular Conformation Neoplasm Transplantation Protein Isoforms Protein Kinase Inhibitors (chemical synthesis, pharmacology) Pyrimidines (chemical synthesis, chemistry, pharmacology)

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