sar405838 and Bone-Neoplasms

We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure-activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (K

Topics: Animals; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Bridged Bicyclo Compounds; Cell Line, Tumor; Drug Discovery; Halogenation; Humans; Indoles; Leukemia; Mice; Molecular Docking Simulation; Neoplasms; Osteosarcoma; Proto-Oncogene Proteins c-mdm2; Pyrrolidines; Rats; Structure-Activity Relationship

We previously reported the discovery of potent and selective morpholinone and piperidinone inhibitors of the MDM2-p53 interaction. These inhibitors have in common a carboxylic acid moiety that engages in an electrostatic interaction with MDM2-His96. Our continued search for potent and diverse inhibitors led to the discovery of novel replacements for these acids uncovering new interactions with the MDM2 protein. In particular, using pyridine or thiazole as isosteres of the carboxylic acid moiety resulted in very potent analogues. From these, AM-6761 (4) emerged as a potent inhibitor with remarkable biochemical (HTRF IC50 = 0.1 nM) and cellular potency (SJSA-1 EdU IC50 = 16 nM), as well as favorable pharmacokinetic properties. Compound 4 also shows excellent antitumor activity in the SJSA-1 osteosarcoma xenograft model with an ED50 of 11 mg/kg. Optimization efforts toward the discovery of these inhibitors as well as the new interactions observed with the MDM2 protein are described herein.

Topics: Acetates; Animals; Antineoplastic Agents; Bone Neoplasms; Carboxylic Acids; Cell Proliferation; Cells, Cultured; Crystallography, X-Ray; Drug Design; Female; Humans; Hydrogen Bonding; Mice; Mice, Nude; Models, Molecular; Molecular Structure; Myocytes, Smooth Muscle; Osteosarcoma; Piperidones; Protein Binding; Protein Interaction Domains and Motifs; Proto-Oncogene Proteins c-mdm2; Stereoisomerism; Structure-Activity Relationship; Tumor Cells, Cultured; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays