| Autor: |
Hardcastle, I. R., Arris, C. E., Bentley, J., Boyle, F. T., Chen, Y., Curtin, N. J., Endicott, J. A., Gibson, A. E., Golding, B. T., Griffin, R. J., Jewsbury, P., Menyerol, J., Mesguiche, V., Newell, D. R., Noble, M. E. M., Pratt, D. J., Wang, L.-Z., Whitfield, H. J. |
| Zdroj: |
Journal of Medicinal Chemistry; July 2004, Vol. 47 Issue: 15 p3710-3722, 13p |
| Abstrakt: |
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. |
| Databáze: |
Supplemental Index |
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