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N 2 -Substituted O 6 -Cyclohexylmethylguanine Derivatives: Potent Inhibitors of Cyclin-Dependent Kinases 1 and 2

2004; American Chemical Society; Volume: 47; Issue: 15 Linguagem: Inglês

10.1021/jm0311442

1520-4804

Ian R. Hardcastle, Christine E. Arris, Johanne Bentley, F. Thomas Boyle, Y. Chen, Nicola J. Curtin, Jane Endicott, Ashleigh E. Gibson, Bernard T. Golding, Roger J. Griffin, Philip J. Jewsbury, Jerome Menyerol, Véronique Mesguiche, David R. Newell, M.E.M. Noble, D.J. Pratt, Lan-Zhen Wang, Hayley J. Whitfield,

HIV/AIDS drug development and treatment

The adenosine 5'-triphosphate (ATP) competitive cyclin-dependent kinase inhibitor O6-cyclohexylmethylguanine (NU2058, 1) has been employed as the lead in a structure-based drug discovery program resulting in the discovery of the potent CDK1 and -2 inhibitor NU6102 (3, IC50 = 9.5 nM and 5.4 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). The SAR for this series have been explored further by the synthesis and evaluation of 45 N2-substituted analogues of NU2058. These studies have confirmed the requirement for the hydrogen bonding N2-NH group and the requirement for an aromatic N2-substituent to confer potency in the series. Additional potency is conferred by the presence of a group capable of donating a hydrogen bond at the 4'-position, for example, the 4'-hydroxy derivative (25, IC50 = 94 nM and 69 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), 4'-monomethylsulfonamide derivative (28, IC50 = 9 nM and 7.0 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively), and 4'-carboxamide derivative (34, IC50 = 67 nM and 64 nM vs CDK1/cyclinB and CDK2/cyclinA3, respectively). X-ray crystal structures have been obtained for key compounds and have been used to explain the observed trends in activity.