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.
MeSH terms
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Amides / chemistry*
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Cell Line, Tumor
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Chemistry, Physical / methods
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Crystallography, X-Ray
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Cyclin-Dependent Kinase Inhibitor Proteins / chemistry*
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Cyclin-Dependent Kinase Inhibitor Proteins / pharmacology
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Drug Design
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / metabolism
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Humans
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Imidazoles / chemical synthesis*
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Imidazoles / pharmacology
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Infusions, Intravenous
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Models, Chemical
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Molecular Conformation
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Neoplasm Transplantation
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Protein Isoforms
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Protein Kinase Inhibitors / chemical synthesis*
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Protein Kinase Inhibitors / pharmacology
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
Substances
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AZD5597
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Amides
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Cyclin-Dependent Kinase Inhibitor Proteins
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Imidazoles
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KCNH2 protein, human
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Protein Isoforms
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Protein Kinase Inhibitors
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Pyrimidines