Novel Antibacterial Class

We report the discovery and characterization of a novel ribosome inhibitor (NRI) class that exhibits selective and broad-spectrum antibacterial activity. Compounds in this class inhibit growth of many gram-positive and gram-negative bacteria, including the common respiratory pathogens Streptococcus pneumoniae, Haemophilus influenzae, Staphylococcus aureus, and Moraxella catarrhalis, and are nontoxic to human cell lines. The first NRI was discovered in a high-throughput screen designed to identify inhibitors of cell-free translation in extracts from S. pneumoniae. The chemical structure of the NRI class is related to antibacterial quinolones, but, interestingly, the differences in structure are sufficient to completely alter the biochemical and intracellular mechanisms of action. Expression array studies and analysis of NRI-resistant mutants confirm this difference in intracellular mechanism and provide evidence that the NRIs inhibit bacterial protein synthesis by inhibiting ribosomes. Furthermore, compounds in the NRI series appear to inhibit bacterial ribosomes by a new mechanism, because NRI-resistant strains are not cross-resistant to other ribosome inhibitors, such as macrolides, chloramphenicol, tetracycline, aminoglycosides, or oxazolidinones. The NRIs are a promising new antibacterial class with activity against all major drug-resistant respiratory pathogens

Discovery of Potent and Simplified Piperidinone-Based Inhibitors of the MDM2–p53 Interaction

Continued optimization of the N-substituent in the piperidinone series provided potent piperidinone–pyridine inhibitors <b>6</b>, <b>7</b>, <b>14</b>, and <b>15</b> with improved pharmacokinetic properties in rats. Reducing structure complexity of the <i>N</i>-alkyl substituent led to the discovery of <b>23</b>, a potent and simplified inhibitor of MDM2. Compound <b>23</b> exhibits excellent pharmacokinetic properties and substantial in vivo antitumor activity in the SJSA-1 osteosarcoma xenograft mouse model

Rational Design and Binding Mode Duality of MDM2–p53 Inhibitors

Structural analysis of both the MDM2–p53 protein–protein interaction and several small molecules bound to MDM2 led to the design and synthesis of tetrasubstituted morpholinone <b>10</b>, an MDM2 inhibitor with a biochemical IC₅₀ of 1.0 μM. The cocrystal structure of <b>10</b> with MDM2 inspired two independent optimization strategies and resulted in the discovery of morpholinones <b>16</b> and <b>27</b> possessing distinct binding modes. Both analogues were potent MDM2 inhibitors in biochemical and cellular assays, and morpholinone <b>27</b> (IC₅₀ = 0.10 μM) also displayed suitable PK profile for in vivo animal experiments. A pharmacodynamic (PD) experiment in mice implanted with human SJSA-1 tumors showed p21^WAF1 mRNA induction (2.7-fold over vehicle) upon oral dosing of <b>27</b> at 300 mg/kg

Discovery of AM-7209, a Potent and Selective 4‑Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction

Structure-based rational design and extensive structure–activity relationship studies led to the discovery of AMG 232 (<b>1</b>), a potent piperidinone inhibitor of the MDM2–p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of <b>1</b>, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (<b>25</b>), featuring improved potency (<i>K</i>_D from ITC competition was 38 pM, SJSA-1 EdU IC₅₀ = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED₅₀ = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED₅₀ = 10 mg/kg QD). In addition, <b>25</b> possesses distinct mechanisms of elimination compared to <b>1</b>