title: Synthesis and evaluation of aryl thioxothiazolidinone inhibitors of ADAMTS-5 (Aggrecanase-2).
abstract: 5-Benzylidene-2-thioxo-thiazolidin-4-one inhibitors of ADAMTS-5 (Aggrecanase-2) have been prepared via commercially available starting materials. The identified compounds show micromolar ADAMTS-5 potency and demonstrate SAR trends for both the aryl group and thioxothiazolidinone zinc chelator. This series of compounds represents steps toward a metalloprotease inhibitor as a disease-modifying osteoarthritis drug.
authors.affiliation: Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. Bursavm@wyeth.com
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Bursavich
authors.forename: Adam M
authors.initials: AM
authors.lastname: Gilbert
authors.forename: Sabrina
authors.initials: S
authors.lastname: Lombardi
authors.forename: Katy E
authors.initials: KE
authors.lastname: Georgiadis
authors.forename: Erica
authors.initials: E
authors.lastname: Reifenberg
authors.forename: Carl R
authors.initials: CR
authors.lastname: Flannery
authors.forename: Elisabeth A
authors.initials: EA
authors.lastname: Morris
mesh_terms: D051722:ADAM Proteins / Q000037:antagonists & inhibitors*; D000071116:ADAMTS5 Protein; D002614:Chelating Agents; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D045726:Metalloproteases / Q000037:antagonists & inhibitors; D010003:Osteoarthritis / Q000188:drug therapy; D013329:Structure-Activity Relationship; D045162:Thiazolidinediones / Q000138:chemical synthesis* / Q000494:pharmacology*; D015032:Zinc
chemical_list: D002614:Chelating Agents; D004791:Enzyme Inhibitors; D045162:Thiazolidinediones; D045726:Metalloproteases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D015032:Zinc