RESUMO
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.
Assuntos
Amidas/química , Proteínas Inibidoras de Quinase Dependente de Ciclina/química , Imidazóis/síntese química , Inibidores de Proteínas Quinases/síntese química , Pirimidinas/química , Linhagem Celular Tumoral , Físico-Química/métodos , Cristalografia por Raios X , Proteínas Inibidoras de Quinase Dependente de Ciclina/farmacologia , Desenho de Fármacos , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Imidazóis/farmacologia , Infusões Intravenosas , Modelos Químicos , Conformação Molecular , Transplante de Neoplasias , Isoformas de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Pirimidinas/farmacologiaRESUMO
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.