IDENTIFICATION OF A NOVEL CHEMICAL-SERIES THAT BLOCKS INTERLEUKIN-1-STIMULATED METALLOPROTEASE ACTIVITY IN CHONDROCYTES

Cartilage destruction is one of the essential features of osteoarthrit is and other degenerative disease conditions of articular disease, and it may be caused by metalloproteases induced by cytokines such as int erleukin-1. To search for novel chemical entities that will block the production of metalloproteases, we have utilized an in vitro system in which macrophage-conditioned medium (a source of interleukin-1) was u sed to stimulate rabbit articular chondrocytes in culture. Upon treatm ent with macrophage-conditioned medium or recombinant interleukin-1, c hondrocytes synthesize and secrete collagenase, stromelysin and other proteases into the surrounding medium and fail to organize an appropri ate extracellular matrix. Using this in vitro system, we have determin ed that a series of naphthopyran derivatives were able to block the pr oduction of neutral metalloproteases. Structural modifications of the lead compound have revealed specific requirements for activity. This c lass of compounds represents one of very few that are known to block t he synthesis, rather than the activity, of matrix-degrading metallopro teases and thus may be beneficial in preventing the cartilage destruct ion associated with several degenerative diseases of the articular joi nt.