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Bioorg Med Chem Lett. 2014 Aug 15;24(16):3782-5. doi: 10.1016/j.bmcl.2014.06.073. Epub 2014 Jul 1.

Optimization beyond AMG 232: discovery and SAR of sulfonamides on a piperidinone scaffold as potent inhibitors of the MDM2-p53 protein-protein interaction.

Author information

1
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
2
Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. Electronic address: jiangz@amgen.com.
3
Department of Pharmacokinetics and Drug Metabolism, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA.
4
Department of Therapeutic Discovery, Amgen Inc., 360 Binney Street, Cambridge, MA 02142, USA.
5
Department of Oncology Research, Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA.

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.

KEYWORDS:

MDM2; Piperidinone; Protein–protein interaction; Sulfonamide; p53

PMID:
25042256
DOI:
10.1016/j.bmcl.2014.06.073
[Indexed for MEDLINE]

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