Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1997-10-14
1999-06-22
Burn, Brian M.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
562439, A01N 3712
Patent
active
059143487
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a novel Substance FA-70D, which has protease inhibitory activity and is useful as a medicine or to a salt thereof.
BACKGROUND ART
As a group of enzymes produced intracellularly, cathepsin series proteases (cathepsin B, cathepsin L, cathepsin H, etc.) are discharging a variety of physiological functions both intracellularly and extracellularly. For example, it is thought that intracellularly those enzymes are involved in the processing of proteins, decomposition of unwanted proteins, and apoptosis, while extracellularly they are associated with the decomposition of extracellular matrices such as degradation of bone matrix collagen and digestion of infecting bacteria.
Cathepsin L, in particular, is known to have very strong collagen degrading activity and it has been demonstrated in experimental animals, too, that inhibitors of cathepsin L exhibit marked inhibitory effects on the decomposition of bone collagen. Any substance that inhibits cathepsin L specifically is considered to be a promising drug for the therapy of osteoporosis (FEBS Letters, 269 (1), 189-193, 1990). Moreover, such a specific inhibitor of cathepsin L is considered to be a promising drug for the therapy of hypercalcemia.
Cathepsin B is an enzyme which is said to be etiologically associated, in a large measure, with inflammations, cancer metastases, myodystrophy and the like. Recent years have witnessed an increasing number of reports pointing out the correlation between the malignancy of cancer, such as metastasis and invasion, and cathepsin B activity (Cancer Research, 52, 3610-3614, 1992).
For treating diseases associated with cathepsin series proteases, specific inhibitors of those enzymes are needed today but no satisfactory substance has been discovered as yet. Particularly, there is not available a specific inhibitor of the cathepsin associated with bone resorption in osteoporosis.
The present invention has for its object to produce a substance having excellent cathepsin inhibitory activity by utilizing microorganisms.
DISCLOSURE OF THE INVENTION
The inventors of the present invention isolated a large number of microorganisms from the natural soil and screened them for those substances, among metabolites they produce, which would inhibit cathepsin series proteases. As a result, the inventors discovered a substance having cathepsin series protease inhibitory activity in cultures of a strain of microorganism belonging to Actinomycetes, designated FA-70 strain, isolated the substance, and determined its physicochemical properties and structure. The present invention has been developed on the basis of the findings.
As compounds produced by microorganisms and structurally resembling the compound of the present invention, there have been reported Mer-N5075A (Japanese Unexamined Patent Application No.100588/1994; The Journal of Antibiotics, 46, 1622-1624, 1993), .alpha.-MAPI and .beta.-MAPI (Agricultural and Biological Chemistry, 43, 243-250, 1979; Tetrahedron Letters, (7), 625-628, 1979), and GE20372 Factor A and B (The Journal of Antibiotics, 48, 332-334, 1995). However, Substance FA-70D of the present invention is a novel compound structurally corresponding to a citrulline molecule linked by peptide bonding. The compound of the present invention is of value as a cathepsin L inhibitor or a medicine such as a therapeutic drug for osteoporosis.
The present invention, therefore, is directed to Substance FA-70D of the following formula (1) or a salt thereof. ##STR2##
In another aspect, the present invention is directed to a process for producing Substance FA-70D or a salt thereof which comprises cultivating a strain of microorganism belonging to the genus Streptomyces and capable of producing said Substance FA-70D in a culture medium to cause the strain to elaborate and accumulate the substance in the culture broth and harvesting the substance from said broth.
In further aspects, the present invention is directed to a medicine, a therapeutic drug for osteoporosis or a cathepsin L inhibit
Katsunuma Nobuhiko
Kitano Shizuo
Otani Toshio
Sasaki Toru
Wu Yun
Burn Brian M.
Davis Brian J.
Taiho Pharmaceutical Co. Ltd.
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