Carboxy-peptidyl derivatives as antidegenerative active agents

Details Carboxy-peptidyl derivatives as antidegenerative active agents Carboxy-peptidyl derivatives as antidegenerative active agents

1995-05-17

1997-09-30

Ford, John M.

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

514 20, 514330, 514375, 514367, 514394, 514416, 562450, 562574, 548152, 548217, 5483044, 548486, 548400, 548146, 548206, 548252, 548254, 548336, 548357, 548215, 548240, 546245, 546152, 549491, 549498, 549 29, 549 65, 549 69, 549462, 549 49, 544295, 544296, 544264, 544336, 544357, A61K 3702, C07C25906, C07C23752, C07D27762

Patent

active

056725833

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

Novel Carboxy-peptidyl compounds of formula I are found to be useful inhibitors of matrix metalloendoproteinase-mediated diseases. ##STR2##
The disability observed in osteoarthritis (OA) and rheumatoid arthritis (RA) is largely due to the loss of articular cartilage. No therapeutic agent in the prior art is known to prevent the attrition of articular cartilage in these diseases.
"Disease modifying antirheumatic drugs" (DMARD), i.e., agents capable of preventing or slowing the ultimate loss of joint function in OA and RA are widely sought. Generic nonsteroidal antiinflammatory drugs (NSAIDs) may be combined with such agents to provide some relief from pain and swelling.
Stromelysin (aka. proteoglycanase, matrix metalloproteinase-3, MMP-3, procollagenase activator, "transin"), collagenase (aka. interstitial collagenase, matrix metalloproteinase-1 (MMP-1)), and gelatinase (aka. type IV collagenase, matrix metalloproteinase-2, MMP-2, 72kDa-gelatinase or type V collagenase, matrix metalloproteinase-9, MMP-9, 95kDa-gelatinase) are metalloendoproteinases secreted by fibroblasts and chondrocytes, and are capable of degrading the major connective tissue components of articular cartilage or basement membranes. Elevated levels of both enzymes have been detected in joints of arthritic humans and animals: K. A. Hasty, R. A. Reife, A. H. Kang, J. M. Stuart, "The role of stromelysin in the cartilage destruction that accompanies inflammatory arthritis", Arthr. Rheum., 33, 388-97 (1990); S. M. Krane, E. P. Amento, M. B. Goldring, S. R. Goldring, and M. L. Stephenson, "Modulation of matrix synthesis and degradation in joint intimation", The Control of Tissue Damage", A. B. Glauert (ed.), Elsevier Sci. Publ., Amsterdam, 1988, Ch. 14, pp 179-95; A. Blanckaert, B. Mazieres, Y. Eeckhout, G. Vaes, "Direct extraction and assay of collagenase from human osteoarthrtic cartilage", Clin. Chim. Acta, 185 73-80 (1989). Each enzyme is secreted from these cells as an inactive proenzyme which is subsequently activated. There is evidence that stromelysin may be the in vivo activator for collagenase, implying a cascade for degradative enzyme activity: A. Ho, H. Nagase, "Evidence that human rheumatoid synovial matrix metalloproteinase 3 is an endogenous activator of procollagenase", Arch Biochem Biophys., 267, 211-16 (1988); G. Murphy, M. I. Crockett, P. E. Stephens, B. J. Smith, A. J. P. Docherty, "Stromelysin is an activator of procollagenase", Biochem. J., 248, 265-8 (1987); Y. Ogata, J. J. Engh. ld, H. Nagase, "Matrix metalprotease-3 (stromelysin) activates the precusor for human matrix metaloproteinase-9, "J. Biol. Chem. 267, 3581-84 (1992). Inhibiting stromelysin could limit the activation of collagenase and gelatinase as well as prevent the degradation of proteoglycan.
That stromelysin inhibition may be effective in preventing articular cartilage degradation has been demonstrated in vitro by measuring the effect of matrix metalloendoproteinase inhibitors on proteoglycan release from rabbit cartilage explants: C. B. Caputo, L. A. Sygowski, S. P. Patton, D. J. Wolanin, A. Shaw, R. A. Roberts, G. DiPasquale, J. Orthopaedic Res., 6, 103-8 (1988).
There is an extensive literature on the involvement of these metalloproteinases in arthritis, but there is very little to guide one in developing a specific inhibitor for each enzyme.
In preliminary studies of rabbit proteoglycanase with substrates and inhibitors, little was found to indicate the enzyme's requirements for hydrolysis or inhibition beyond a preference for hydrophobic residues at the P.sub.1 ' position: A. Shaw, R. A. Roberts, D. J. Wolanin, "Small substrates and inhibitors of the metalloproteoglycanase of rabbit articular chondrocytes", Adv. Inflam. Res., 12, 67-79 (1988). More extensive studies with a series of substrates revealed that stromelysin will tolerate nearly every amino acid residue around the scissile bond: S. J. Netzel-Arnett, G. B. Fields, H. Nagase, K. Suzuki, W. G. I. Moore, H. Brikedal-Hansen, H. E. Van Wart, Comparative sequence Specif

REFERENCES:
patent: 4511504 (1985-04-01), McCullagh et al.
patent: 4568666 (1986-02-01), McCullagh et al.
patent: 4771037 (1988-09-01), Roberts et al.
patent: 4935404 (1990-06-01), Hunger et al.
patent: 4937243 (1990-06-01), Markwell et al.
patent: 5047400 (1991-09-01), Vincent et al.
patent: 5095119 (1992-03-01), Ocain et al.
Kitazawa, et al., Chem. Abstracts, vol. 115, No. 21, Ab.No.231890z (1991).
Kitazawa, et al., Chem. Abstracts, vol. 117, No. 13, p. 716, Ab. No. 130935d (1992).
Baker et al., Nonpeptide Renin Inhibitors Employing a Novel 3-Aza(or oxo)-2,4-dialkyl Glutonic Acid Moiety as a P2/P3 Amide Bond Replacement. J. Med. Chem. (1992) 35, 1722-1734.

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