Download MendeleyOptimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.
Wang, Y., Zhu, J., Liu, J.J., Chen, X., Mihalic, J., Deignan, J., Yu, M., Sun, D., Kayser, F., McGee, L.R., Lo, M.C., Chen, A., Zhou, J., Ye, Q., Huang, X., Long, A.M., Yakowec, P., Oliner, J.D., Olson, S.H., Medina, J.C.(2014) Bioorg Med Chem Lett 24: 3782-3785
- PubMed: 25042256
- DOI: https://doi.org/10.1016/j.bmcl.2014.06.073
- Primary Citation of Related Structures:
4QOC - PubMed Abstract:
We recently reported on the discovery of AMG 232, a potent and selective piperidinone inhibitor of the MDM2-p53 interaction. AMG 232 is being evaluated in human clinical trials for cancer. Continued exploration of the N-alkyl substituent of this series, in an effort to optimize interactions with the MDM2 glycine-58 shelf region, led to the discovery of sulfonamides such as compounds 31 and 38 that have similar potency, hepatocyte stability and rat pharmacokinetic properties to AMG 232.
Organizational Affiliation:
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
