Author/Authors :
Clifford D. Jones، نويسنده , , David M. Andrews، نويسنده , , Andrew J. Barker، نويسنده , , Kevin Blades، نويسنده , , Paula Daunt، نويسنده , , Simon East، نويسنده , , Catherine Geh، نويسنده , , Mark A. Graham، نويسنده , , Keith M. Johnson، نويسنده , , Sarah A. Loddick، نويسنده , , Heather M. McFarland، نويسنده , , Alexandra McGregor، نويسنده , , Louise Moss، نويسنده , , David A. Rudge، نويسنده , , Peter B. Simpson، نويسنده , , Michael L. Swain، نويسنده , , Kin Y. Tam، نويسنده , , Julie A. Tucker and Ric، نويسنده , , Mike Walker، نويسنده ,
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 (iv) dosing was selected for further development as AZD5597.
Keywords :
Imidazole amide , Cyclin-dependent kinase , Anti-cancer , CDK , kinase inhibitor , Cell cycle , kinase
