Identification of a novel chemical series that blocks interleukin-1-stimulated metalloprotease activity in chondrocytes.
Cartilage destruction is one of the essential features of osteoarthritis and other degenerative disease conditions of articular disease, and it may be caused by metalloproteases induced by cytokines such as interleukin-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 used to stimulate rabbit articular chondrocytes in culture. Upon treatment with macrophage-conditioned medium or recombinant interleukin-1, chondrocytes synthesize and secrete collagenase, stromelysin and other proteases into the surrounding medium and fail to organize an appropriate extracellular matrix. Using this in vitro system, we have determined that a series of naphthopyran derivatives were able to block the production of neutral metalloproteases. Structural modifications of the lead compound have revealed specific requirements for activity. This class of compounds represents one of very few that are known to block the synthesis, rather than the activity, of matrix-degrading metalloproteases and thus may be beneficial in preventing the cartilage destruction associated with several degenerative diseases of the articular joint.
Chandrasekhar
S
S
Endocrine Research Division Lilly Research Laboratories, Indianapolis, Indiana, USA.
Harvey
A K
AK
Dell
C P
CP
Ambler
S J
SJ
Smith
C W
CW
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned; D003513:Cycloheximide / Q000494:pharmacology; D004789:Enzyme Activation; D004790:Enzyme Induction; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D009584:Nitrogen / Q000737:chemistry; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship
D017077:Culture Media, Conditioned; D007375:Interleukin-1; C094200:LY 290181; D009281:Naphthalenes; D011714:Pyrans; D003513:Cycloheximide; D008666:Metalloendopeptidases; D009584:Nitrogen