Anti-arthritic activity of hydroxamic acid-based pseudopeptide inhibitors of matrix metalloproteinases and TNF alpha processing.
OBJECTIVE
The effects of two hydroxamate inhibitors of metalloproteinase and tumor necrosis factor alpha (TNF alpha) processing on endotoxin-induced plasma TNF alpha and arthritic lesions in adjuvant-induced arthritic (AA) rats were determined.


METHODS
BB-1101 and BB-1433 were administered orally twice daily to AA Lewis rats with an established disease (days 13 to 22). AA rats (day 16) or normal rats were injected with bacterial endotoxin and plasma levels of TNF alpha were also determined.


METHODS
Hindpaw swelling was measured plethysmographically. Bone degradation was determined by radiography and bone mineral densitometry. TNF alpha was quantified using a sandwich ELISA.


RESULTS
The hydroxamic-acid pseudopeptides inhibited plasma. TNF alpha levels in vivo and significantly reduced swelling and bone degradation of the tibiotarsal joints of AA rats in the range of 10-50 mg/kg given orally (p < 0.01 by Student's t-test).


CONCLUSIONS
Thus, these novel compounds offer a new disease modifying therapy for arthritis and the results also suggest that inhibition of TNF alpha production may contribute, at least in part, to their anti-arthritic activity.
DiMartino
M
M
SmithKline Beecham Pharmaceuticals (UW2109), King of Prussia, PA 19406, USA.
Wolff
C
C
High
W
W
Stroup
G
G
Hoffman
S
S
Laydon
J
J
Lee
J C
JC
Bertolini
D
D
Galloway
W A
WA
Crimmin
M J
MJ
Davis
M
M
Davies
S
S
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy*; D001593:Benzyl Compounds; D003907:Dexamethasone / Q000494:pharmacology*; D004338:Drug Combinations; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors*; D010431:Pentoxifylline / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011917:Rats, Inbred Lew; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
C101468:BB 1101; D001593:Benzyl Compounds; D004338:Drug Combinations; D006877:Hydroxamic Acids; D011480:Protease Inhibitors; D013386:Succinates; D014409:Tumor Necrosis Factor-alpha; D003907:Dexamethasone; D008666:Metalloendopeptidases; D010431:Pentoxifylline