title: Inhibition of interleukin-1 (IL-1) induced neutral proteases from rabbit articular chondrocytes by WY-46,135 and WY-48,989.
abstract: The effects of potential anti-osteoarthritic compounds both on the direct inhibition of collagenase and neutral protease activities and on IL-1 induced release of neutral proteases from rabbit articular chondrocytes were investigated. WY-46,135 ((+)-N-[[[(5-chloro-2-benzothiazolyl)thio]phenyl]acetyl]-L- cysteine) directly inhibited collagenase activity (IC50 = 15.4 microM). This inhibition was reversible upon dialysis. WY-46,135 also directly inhibited neutral protease activity (IC50 = 16.8 microM) but did not significantly block bacterial collagenase activity at a concentration of 80 microM. In contrast, WY-48,989 (4-[[2-(7-chloro-2-phenyl-2H-pyrazolo[4,3-c]quinolin-4- yl)ethyl]amino]benzonitrile) did not directly inhibit either collagenase (10 microM) or neutral protease (100 microM) activity. Both WY-48,989 and WY-46,135 inhibited IL-1 stimulated release of neutral proteases (IC50 = 3 microM). The activities of these compounds represents two potential approaches for the treatment of osteoarthritis. WY-46,135 combines direct metalloprotease inhibitory activity with the inhibition of IL-1 stimulated neutral protease release from articular chondrocytes while WY-48,989 selectively inhibits the IL-1 induced release of metalloproteases.
authors.affiliation: Wyeth-Ayerst Research, Princeton, N.J. 08540.
authors.forename: R G
authors.initials: RG
authors.lastname: Caccese
authors.forename: J F
authors.initials: JF
authors.lastname: DiJoseph
authors.forename: J S
authors.initials: JS
authors.lastname: Skotnicki
authors.forename: L E
authors.initials: LE
authors.lastname: Borella
authors.forename: L M
authors.initials: LM
authors.lastname: Adams
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives*; D000818:Animals; D052160:Benzothiazoles; D002358:Cartilage, Articular / Q000201:enzymology* / Q000473:pathology; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D010450:Endopeptidases / Q000032:analysis / Q000096:biosynthesis; D004790:Enzyme Induction / Q000187:drug effects; D006614:Hindlimb; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000494:pharmacology*; D008297:Male; D003012:Microbial Collagenase / Q000032:analysis; D011480:Protease Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011817:Rabbits
chemical_list: D052160:Benzothiazoles; D007375:Interleukin-1; C046256:N-((((5-chloro-2-benzothiazolyl)thio)phenyl)acetyl)cysteine; D011480:Protease Inhibitors; D011720:Pyrazoles; C073134:WY 48989; D010450:Endopeptidases; D003012:Microbial Collagenase; D003545:Cysteine; D000111:Acetylcysteine