Design strategies for the identification of MMP-13 and Tace inhibitors.
Inhibitors of matrix metalloprotease (MMP)-13 and tumor necrosis factor-alpha converting enzyme (TACE) have been highly sought as potential therapeutic agents for the treatment of osteoarthritis and rheumatoid arthritis, respectively. This review focuses on the published literature on these inhibitors from 2001 to mid-2003. Significant advances have been reported in the design and synthesis of potent and selective inhibitors of MMP-13 using hydroxamic acid and non-hydroxamate zinc chelators on a variety of scaffolds. TACE inhibitors based on variations of known MMP inhibitors scaffolds and novel designs have been reported. Selectivity profiles for these inhibitors range from broad-spectrum to TACE-specific. Future clinical studies on these and other inhibitors will determine which MMP, or set of MMPs, must be inhibited for efficacy and long-term safety.
Skotnicki
Jerauld S
JS
Wyeth Research Chemical and Screening Sciences, 401 N Middletown Road, Pearl River, New York, NY 10965, USA. skotnij@wyeth.com
DiGrandi
Martin J
MJ
Levin
Jeremy I
JI
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D001172:Arthritis, Rheumatoid / Q000188:drug therapy; D002614:Chelating Agents; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis; D053509:Matrix Metalloproteinase 13; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010003:Osteoarthritis / Q000188:drug therapy; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship; D015032:Zinc
D002614:Chelating Agents; D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D051722:ADAM Proteins; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; D015032:Zinc