Selective and potent morpholinone inhibitors of the MDM2-p53 protein-protein interaction.
J Med Chem
; 57(6): 2472-88, 2014 Mar 27.
Article
in En
| MEDLINE
| ID: mdl-24548297
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Morpholines
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Tumor Suppressor Protein p53
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Proto-Oncogene Proteins c-mdm2
/
Acetates
/
Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
J Med Chem
Journal subject:
QUIMICA
Year:
2014
Document type:
Article
Affiliation country:
United States