Heteroaryl-fused 2-phenylisothiazolone inhibitors of cartilage breakdown.
The synthesis, biological evaluation, and structure-activity relationships of a series of N-phenyl heteroaryl-fused isothiazolones are described. These isothiazolones have been shown to exhibit potent, dose-dependent inhibition of IL-1 beta-induced breakdown of proteoglycan in a cartilage organ culture assay. This effect is likely due to inhibition of MMP activation and a consequent reduction in MMP activity following IL-1 beta stimulation. Thus these compounds potentially represent simple, non-peptidic disease-modifying agents for the treatment of arthritic diseases. To examine the effects of structure on in vitro activity, three general features of the molecules were varied, substituents on the pendant N-phenyl group, the position of ring fusion to the isothiazolone, and substituents on the fused ring peri to the isothiazolone sulfur.
Wright
S W
SW
DuPont Merck Pharmaceutical Company, Wilmington, Delaware 19880-0353.
Petraitis
J J
JJ
Abelman
M M
MM
Batt
D G
DG
Bostrom
L L
LL
Corbett
R L
RL
Decicco
C P
CP
Di Meo
S V
SV
Freimark
B
B
Giannaras
J V
JV
D000818:Animals; D002356:Cartilage / Q000187:drug effects* / Q000378:metabolism*; D002417:Cattle; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000633:toxicity; D007536:Isomerism; D008297:Male; D008666:Metalloendopeptidases / Q000494:pharmacology; D008954:Models, Biological; D011509:Proteoglycans / Q000378:metabolism; D011725:Pyridines / Q000138:chemical synthesis / Q000494:pharmacology; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
D007375:Interleukin-1; D011509:Proteoglycans; D011725:Pyridines; D011743:Pyrimidines; D013844:Thiazoles; D008666:Metalloendopeptidases