Abstract
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
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Acetates / chemical synthesis*
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Acetates / pharmacology*
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Animals
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Antineoplastic Agents / chemical synthesis*
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Antineoplastic Agents / pharmacology*
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Cell Line, Tumor
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Crystallography, X-Ray
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Drug Discovery
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Humans
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Indicators and Reagents
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Mice
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Models, Molecular
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Molecular Conformation
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Morpholines / chemical synthesis*
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Morpholines / pharmacokinetics
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Morpholines / pharmacology*
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Proto-Oncogene Proteins c-mdm2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-mdm2 / chemistry*
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Rats
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Structure-Activity Relationship
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Tumor Suppressor Protein p53 / antagonists & inhibitors*
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Tumor Suppressor Protein p53 / chemistry*
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Xenograft Model Antitumor Assays
Substances
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2-(4-(2-(tert-butylsulfonyl)-1-cyclopropylethyl)-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl)acetic acid
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Acetates
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Antineoplastic Agents
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Indicators and Reagents
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Morpholines
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-mdm2