Synthesis and evaluation of aryl thioxothiazolidinone inhibitors of ADAMTS-5 (Aggrecanase-2).
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.
Bursavich
Matthew G
MG
Exploratory Medicinal Chemistry, Chemical and Screening Sciences, Wyeth Research, 401 North Middletown Road, Pearl River, NY 10965, USA. Bursavm@wyeth.com
Gilbert
Adam M
AM
Lombardi
Sabrina
S
Georgiadis
Katy E
KE
Reifenberg
Erica
E
Flannery
Carl R
CR
Morris
Elisabeth A
EA
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
D002614:Chelating Agents; D004791:Enzyme Inhibitors; D045162:Thiazolidinediones; D045726:Metalloproteases; D051722:ADAM Proteins; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human; D015032:Zinc