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.
Subject(s)
Amides/chemistry , Cyclin-Dependent Kinase Inhibitor Proteins/chemistry , Imidazoles/chemical synthesis , Protein Kinase Inhibitors/chemical synthesis , Pyrimidines/chemistry , Cell Line, Tumor , Chemistry, Physical/methods , Crystallography, X-Ray , Cyclin-Dependent Kinase Inhibitor Proteins/pharmacology , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/metabolism , Humans , Imidazoles/pharmacology , Infusions, Intravenous , Models, Chemical , Molecular Conformation , Neoplasm Transplantation , Protein Isoforms , Protein Kinase Inhibitors/pharmacology , Pyrimidines/chemical synthesis , Pyrimidines/pharmacologyABSTRACT
Exploration of the structure-activity relationships of the traditional C-5 acetamidomethyl side chain of the oxazolidonone antibacterials has yielded new, potent series of compounds of which the first examples, the O-linked iosoxazoles are described in detail, leading to the selection of the pre-clinical candidate AZD2563.
