Premium
Design, Synthesis, and Preliminary Biological Evaluation of Pyrrolo[3,4‐ c ]quinolin‐1‐one and Oxoisoindoline Derivatives as Aggrecanase Inhibitors
Author(s) -
Cappelli Andrea,
Nannicini Chiara,
Valenti Salvatore,
Giuliani Germano,
Anzini Maurizio,
Mennuni Laura,
Giordani Antonio,
Caselli Gianfranco,
Stasi Luigi Piero,
Makovec Francesco,
Giorgi Gianluca,
Vomero Salvatore
Publication year - 2010
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200900523
Subject(s) - chemistry , adamts , stereochemistry , docking (animal) , substituent , protein data bank (rcsb pdb) , aggrecanase , derivative (finance) , carboxylate , structure–activity relationship , enzyme , combinatorial chemistry , in vitro , biochemistry , medicine , osteoarthritis , alternative medicine , thrombospondin , articular cartilage , nursing , pathology , metalloproteinase , financial economics , economics
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.