The design and synthesis of aryl hydroxamic acid inhibitors of MMPs and TACE.
Three different classes of aryl hydroxamic acid scaffolds have been explored and provided potent inhibitors of MMP-1, -2, -9, -13 and TACE. Structure-based design has allowed the evolution of these inhibitors from broad spectrum inhibitors into compounds that are more selective for MMPs relevant to particular disease states. Aryl hydroxamates selective for MMP-9, MMP-13 and TACE have been disclosed that may aid in the study of the physiological role of these enzymes. Furthermore, the different selectivity profiles offered by these MMP/TACE inhibitors may allow the determination of which metalloprotease, or group of metalloproteases, must be inhibited for the safe, long-term treatment of osteoarthritis, rheumatoid arthritis and cancer. Some of these compounds have demonstrated useful biological activity in efficacy models relevant to osteoarthritis and rheumatoid arthritis and are therefore potential clinical candidates.
Levin
Jeremy I
JI
Wyeth Research, 401 N. Middletown Road, Pearl River, New York, 10965, USA. levinji@wyeth.com
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000818:Animals; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D061965:Matrix Metalloproteinase Inhibitors; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
D006877:Hydroxamic Acids; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human