Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1989-08-04
1992-03-31
Lee, Lester L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530330, A61K 702, C07K 510
Patent
active
051008742
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to new peptidylhydroxamic acid derivatives which specifically inhibit the action of collagenase of vertebrate origin, as well as to collagenase inhibitors containing these new peptidylhydroxamic acid derivatives as active ingredient.
1. Background Art
Collagenase is an enzyme which decomposes collagen, one of the main protein components constituting connective tissues.
Animals in pathological conditions show an abnormal overaction of collagenase in processes of the destruction and repair of tissues. Such abnormal overaction of collagenase is observed, for example, in such cases as rheumatoid arthritis, peridental diseases, corneal ulcer and epidermolysis bullosa, where inhibition of the action of collagenase provides a useful means for treating such diseases.
2. Prior Art
Some peptidylhydroxamic acids have heretofore been known as substances which exhibit inhibitory action on collagenase. Thus, William M. Moore et al. reported benzyloxycarbonyl-prolyl-leucyl-glycylhydroxamic acid (Z-Pro-Leu-Gly-NHOH) (see William M. Moore and Curtis A. Spilburg, Biochemical and Biophysical Research Communications, Vol. 136, No. 1, Pages 390-395, 1986). Furthermore as other peptide-based synthetic collagenase inhibitors were reported mercapto-containing compounds (see Robert D. Gray, Hossain H. Saneii and Arno F. Spatola, Biochemical and Biophysical Research Communications, Vol. 101, No. 4, Pages 1251-1258, 1981; Charles F. Vencill, David Rasnick, Katherine V. Crumley, Norikazu Nishino and James C. Powers, Biochemistry 24, 3149-3157, 1985) or carboxyl group-containing compounds (see Jean-Marie Delaisse, Yves Eeckhout, Christopher Sear, Alan Galloway, Keith McCullagh and Gilbert Vaes, Biochemical and Biophysical Research Communications, Vol. 133, No. 2, Pages 483-490, 1985).
The purpose of the present invention is to provide new peptide compounds which selectively inhibit the action of collagenase derived from vertebrates without inhibiting other protease actions (i.e. which exhibit an inhibitory action of high specificity), and which have low toxicity, improved metabolic rate and other improved properties.
The present inventors, as a result of extensive researches aiming at developing new peptide compounds with such preferable properties have achieved the present invention, according to which it has been found that new peptidylhydroxamic acid derivatives of the general formula (I): acid residue; the carboxyl group of .alpha.-amino acid X.sup.1 forms a peptide bond together with the amino group of .alpha.-amino acid X.sup.2 ; the carboxyl group of .alpha.-amino acid X.sup.2 forms a peptide bond together with the amino group of .alpha.-amino acid X.sup.3 ; the carboxyl group of .alpha.-amino acid X.sup.3 forms a peptide bond together with the amino group of .alpha.-amino acid X.sup.4 and the carboxyl group of .alpha.-amino acid X.sup.4 forms an amido bond together with --NHOH; and the hydrogen atom of the amino group in .alpha.-amino acid X.sup.1 may be replaced by an aliphatic or aromatic carbyloxycarbonyl or acyl group which itself may have substituents, as well as their salts, are suitable for the purpose mentioned above.
The present inventors have succeeded in providing new compounds of the general formula (I) suitable for the purpose mentioned above by using, as an index, inhibitory action on each of the seven enzymes, i.e. collagenase from human fibroblasts, collagenase from tadpoles, collagenase from bacteria, urease, thermolysin, .alpha.-chymotrypsin and trypsin to screen compounds for strong inhibitory action on the first two enzymes.
The preparation of new peptidylhydroxamic acid derivatives of the general formula (I) are carried out by processes which can be divided roughly into (A) and (B) below: starting material; the peptide chain is extended on the Boc-N group side first to form the group X.sup.3 -X.sup.4 -, which is converted, via the group X.sup.2 -X.sup.3 -X.sup.4 - into the group X.sup.1 -X.sup.2 -X.sup.3 -X.sup.4 -; and finally the O-benzyl on the hydro
REFERENCES:
patent: 4568666 (1986-02-01), McCullagh et al.
patent: 4595700 (1986-06-01), Donald et al.
patent: 4599361 (1986-07-01), Dickens et al.
patent: 4681966 (1987-07-01), Donald et al.
patent: 4687841 (1987-08-01), Spilburg et al.
patent: 4720486 (1988-01-01), Spilburg et al.
patent: 4743587 (1988-05-01), Dickens et al.
Morikawa Tadanori
Nagai Yutaka
Obata Masami
Odake Shinjiro
Okayama Toru
Fuji Yakuhin Kogyo Kabushiki Kaisha
Lee Lester L.
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