Design, Synthesis, and Preliminary Biological Evaluation of Pyrrolo[3,4‐c]quinolin‐1‐one and Oxoisoindoline Derivatives as Aggrecanase Inhibitors
A Cappelli, C Nannicini, S Valenti, G Giuliani… - …, 2010 - Wiley Online Library
ChemMedChem, 2010•Wiley Online Library
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 …
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 …
Abstract
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 IC50 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 IC25 values in the micromolar range.
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