Download MendeleyDiscovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2-p53 Interaction.
Yu, M., Wang, Y., Zhu, J., Bartberger, M.D., Canon, J., Chen, A., Chow, D., Eksterowicz, J., Fox, B., Fu, J., Gribble, M., Huang, X., Li, Z., Liu, J.J., Lo, M.C., McMinn, D., Oliner, J.D., Osgood, T., Rew, Y., Saiki, A.Y., Shaffer, P., Yan, X., Ye, Q., Yu, D., Zhao, X., Zhou, J., Olson, S.H., Medina, J.C., Sun, D.(2014) ACS Med Chem Lett 5: 894-899
- PubMed: 25147610
- DOI: https://doi.org/10.1021/ml500142b
- Primary Citation of Related Structures:
4QO4 - PubMed Abstract:
Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone-pyridine inhibitors 6, 7, 14, and 15 with improved pharmacokinetic properties in rats. Reducing structure complexity of the N-alkyl substituent led to the discovery of 23, a potent and simplified inhibitor of MDM2. Compound 23 exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model.
Organizational Affiliation:
Departments of Therapeutic Discovery and Pharmacokinetics and Drug Metabolism, Amgen Inc. , 1120 Veterans Boulevard, South San Francisco, California 94080, United States.
