title: Inhibition of aggrecanases as a therapeutic strategy in osteoarthritis.
abstract: Over the last decade, there has been a large effort to target aggrecanases, which are responsible for the degradation of the aggrecan in the extracellular matrix of joints, in order to hopefully lead to new treatments for osteoarthritis. Only a few inhibitors have been effective in explants or rodent models and thus only a few have reached the clinic, none of which have proven to be effective. In this article, a survey of chemical series is described, covering historical and recent inhibitors and highlighting how some of their problems were resolved, with a critical overview of the challenges encountered. A large effort should be undertaken in designing smaller compounds with higher residence times, defining new interaction sites on the aggrecanases and exploiting target flexibility.
authors.affiliation: INSERM U761 Biostructures & Drug Discovery unit University Lille Nord de France, Institut Pasteur de Lille, rue Laguesse, Lille, F-59000, France.
authors.forename: Jamal
authors.initials: J
authors.lastname: El Bakali
authors.forename: Helene
authors.initials: H
authors.lastname: Gras-Masse
authors.forename: Lucie
authors.initials: L
authors.lastname: Maingot
authors.forename: Benoit
authors.initials: B
authors.lastname: Deprez
authors.forename: Julie
authors.initials: J
authors.lastname: Dumont
authors.forename: Florence
authors.initials: F
authors.lastname: Leroux
authors.forename: Rebecca
authors.initials: R
authors.lastname: Deprez-Poulain
mesh_terms: D004305:Dose-Response Relationship, Drug; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D010003:Osteoarthritis / Q000188:drug therapy* / Q000201:enzymology / Q000378:metabolism; D011480:Protease Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use*; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D010450:Endopeptidases; C083641:aggrecanase