Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – 4 to 5 amino acid residues in defined sequence
Patent
1990-12-07
1992-11-10
Lee, Lester L.
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
4 to 5 amino acid residues in defined sequence
530329, 530331, A61K 3702, A61K 3700, C07K 500, C07K 700
Patent
active
051625008
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to poststatin and related compounds or salts thereof. More specifically, the invention relates to poststatin and related compounds or salts thereof having activities of inhibiting the actions of endopeptidases including those classified as serine enzymes or SH-enzymes. The invention also relates to a process for the preparation of such poststatin compounds, and to a pharmaceutical composition which contains, as active ingredient, the poststatin compounds.
BACKGROUND OF THE INVENTION
Prolylendopeptidase is an example of endopeptidase and exhibits an activity of inactivating the following substances: substance P which is a neuro-conducting substance; thyrotropin-releasing hormone; neurotensin; and vasopressin which seems to have a relation with memories. It is considered that prolylendopeptidase inhibitor substances might have various physiological activities. Particularly, it is observed that a prolylendopeptidase inhibitor substance exhibits an action of inhibiting an inactivation of vasopressin, so that it is expected that this substance might be useful as medicine for the treatment of amnestic syndromes. For instance, Journal of the Japanese Agricultural Chemical Society, 58, 1147-1154 (1984) and Japanese Patent Publication (Laid-open) Nos. 60-172929 (1985) and 60-188317 (1985) disclose that certain prolylendopeptidase inhibitor agents show an anti-amnestic effect. So, it is highly desirable to provide a more effective prolylendopeptidase inhibitor agent which can be used as an anti-amnestic agent.
It is reported by Aoyagi that, from the experimental data concerning the enzyme activity in spleens of NZB/WFl mice sufferring from SLE (systematic lupus erythematosus), it can be said that the amount of prolylendopeptidase increases with a progress of the sick (Journal of Applied Biochemistry, 7, 273-281 (1985)). It is therefore expected that a prolylendopeptidase inhibitor agent might be effective for the treatment of SLE.
It is also known that there are a number of low molecular weight peptidase having an endopeptidase-inhibiting activity. Examples of such low molecular weight peptides are natural peptide aldehydes such as leupeptin and elastatinal. Furthermore, a number of peptide aldehydes have been synthesized as endopeptidase inhibitor agents. According to a theory proposed by Thompson, R. C. (Biochemistry, 12, 47-51 (1973)), such peptide aldehydes are bonded to enzymes, so that the aldehyde radicals of the peptide aldehydes may occupy the sites of the enzymes where they can react with the carbonyl radicals of (substrate) peptide, so as to inhibit the enzyme activity.
Hori et al reported that certain peptides, having an (RS)-3-amino-2-oxo-pentanoic acid ethyl or benzyl ester radical at the C-terminal, can be prepared by a Dakin-West reaction, and that these synthetic peptides inhibit the activity of elastase, which is an example of peptidases (Peptides, Structure and Function, Proceedings of the Ninth American Peptide Symposium, pp. 819-822 (1985)).
DISCLOSURES OF THE INVENTION
As a result of our continuous study on substances which have an endopeptidase-inhibiting activity, we have now found that Streotomyces viridochromogenes strain MH534-30F3 produces a substance which strongly inhibits the above-mentioned enzyme. Furthermore, we have succeeded to isolate and purify the inhibitor substance, and have named the substance as poststatin. Poststatin has a novel structure, wherein the peptide chain has ketone radicals, and also has amino acid residues at both terminals thereof. In addition, we have prepared a number of related compounds with reference to the structure of poststatin, and have found that these related compounds also have an endopeptide-inhibiting activity.
Therefore, in the first aspect of the present invention, there are provided poststatin and related compounds or salts thereof having the formula: ##STR1## wherein X represents a peptide residue which may have functional radicals optionally protected, or X represents an amino acid
REFERENCES:
patent: 4623639 (1986-11-01), Hassall et al.
patent: 4868155 (1989-09-01), Durette et al.
Hori et al., Peptides: Structure and Function, Editor. Deber et al., pp. 819-822, 1985.
Aoyagi Takaaki
Hamada Masa
Muraoka Yasuhiko
Nagai Machiko
Naganawa Hiroshi
Davenport A. M.
Lee Lester L.
Zaidan Hojin Biseibutsu Kagaku Kenkyu Kai
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