Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction.
We previously reported the discovery of AMG 232, a highly potent and selective piperidinone inhibitor of the MDM2-p53 interaction. Our continued search for potent and diverse analogues led to the discovery of novel morpholinone MDM2 inhibitors. This change to a morpholinone core has a significant impact on both potency and ... metabolic stability compared to the piperidinone series. Within this morpholinone series, AM-8735 emerged as an inhibitor with remarkable biochemical potency (HTRF IC50 = 0.4 nM) and cellular potency (SJSA-1 EdU IC50 = 25 nM), as well as pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 41 mg/kg. Lead optimization toward the discovery of this inhibitor as well as key differences between the morpholinone and the piperidinone series will be described herein.
Mesh Terms:
Acetates, Animals, Antineoplastic Agents, Cell Line, Tumor, Crystallography, X-Ray, Drug Discovery, Humans, Indicators and Reagents, Mice, Models, Molecular, Molecular Conformation, Morpholines, Proto-Oncogene Proteins c-mdm2, Rats, Structure-Activity Relationship, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
Acetates, Animals, Antineoplastic Agents, Cell Line, Tumor, Crystallography, X-Ray, Drug Discovery, Humans, Indicators and Reagents, Mice, Models, Molecular, Molecular Conformation, Morpholines, Proto-Oncogene Proteins c-mdm2, Rats, Structure-Activity Relationship, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays
J Med Chem
Date: Mar. 27, 2014
PubMed ID: 24548297
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