2,5-Diarylisothiazolone: novel inhibitors of cytokine-induced cartilage destruction.
A series of 2,5-diarylisothiazolones is reported that inhibit the IL-1 beta-induced breakdown of bovine nasal septum cartilage in an organ culture assay. The synthesis and preliminary SAR of these compounds are described. These compounds represent a novel, nonpeptide lead series approach to the mediation of the chronic cartilage breakdown associated with arthritic disease. These compounds are relatively resistant to reductive metabolism by liver microsomal preparations and appear to inhibit cartilage breakdown by interfering with the proteolytic activation of matrix metalloproteinases.
Wright
S W
SW
Du Pont Merck Pharmaceutical Company, Wilmington, DE 19880, USA.
Petraitis
J J
JJ
Freimark
B
B
Giannaras
J V
JV
Pratta
M A
MA
Sherk
S R
SR
Williams
J M
JM
Magolda
R L
RL
Arner
E C
EC
D000818:Animals; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism; D002417:Cattle; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006868:Hydrolysis; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D009924:Organ Culture Techniques; D010003:Osteoarthritis / Q000378:metabolism / Q000517:prevention & control; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007375:Interleukin-1; D013844:Thiazoles