Design, Synthesis, and Preliminary Biological Evaluation of Pyrrolo[3,4-c]quinolin-1-one and Oxoisoindoline Derivatives as Aggrecanase Inhibitors
| Autor: | Salvatore Vomero, Gianluca Giorgi, Salvatore Valenti, Francesco Makovec, Antonio Giordani, Maurizio Anzini, Gianfranco Caselli, Luigi Piero Stasi, Germano Giuliani, Laura Mennuni, Andrea Cappelli, Chiara Nannicini |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Indoles
Stereochemistry Drug Evaluation Preclinical Molecular Conformation Protein Data Bank (RCSB PDB) Substituent Crystal structure Quinolones Crystallography X-Ray Biochemistry chemistry.chemical_compound Catalytic Domain Endopeptidases Drug Discovery Computer Simulation Protease Inhibitors Carboxylate General Pharmacology Toxicology and Pharmaceutics Binding site Aggrecanase Pharmacology chemistry.chemical_classification Binding Sites Organic Chemistry ADAM Proteins chemistry Docking (molecular) Drug Design Molecular Medicine Tricyclic |
| Zdroj: | ChemMedChem. 5:739-748 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.200900523 |
| Popis: | A small set of aggrecanase inhibitors based on the pyrrolo[3,4-c]quinolin-1-one or oxoisoindoline frameworks bearing a 4-(benzyloxy)phenyl substituent and different zinc binding groups were rationally designed and evaluated in silico by docking studies using the crystal structure of the ADAMTS-5 catalytic domain (PDB code: 3B8Z). The designed compounds were synthesized via straightforward routes and tested for their potential inhibitory activity against ADAMTS-5 and ADAMTS-4. Among the compounds containing the pyrrolo[3,4-c]quinolinone tricyclic system, hydroxamate derivative 2 b inhibited both ADAMTS-5 and ADAMTS-4, with IC(50) values in the submicromolar range and an inhibitory profile very similar to that of reference carboxylate derivative 11. Conversely, the corresponding carboxylate derivative 2 a was significantly less active and unable to discriminate between ADAMTS-5 and -4. The structure-activity relationship analysis of pyrroloquinolinone derivatives 2 a-i suggests that the carboxylate or hydroxamate groups of compounds 2 a,b play a key role in the interaction of these compounds with ADAMTS-5 and -4. On the other hand, the oxoisoindoline derivatives 3 a,b lack significant ADAMTS-4 inhibitory activity and inhibit ADAMTS-5 showing IC(25) values in the micromolar range. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text