Cyclic depsipeptides useful for treatment of hyperlipemia

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai

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514 11, 530317, 530321, 530359, 4352521, C07K 1100, C07K 700, A61K 3808, A61K 3815

Patent

active

058011439

DESCRIPTION:

BRIEF SUMMARY
This application is a 371 of PCT/JP95/01003 filed on May 25, 1995, and claims priority from Japanese Patent Application 6/113023 filed on May 26, 1994.


TECHNICAL FIELD

This invention relates to a cyclic depsipeptide which has an inhibitory activity on the secretion of lipids and an inhibitory activity on the production of apolipoprotein B and can be utilized as a therapeutic agent for hyperlipemia, a process for producing the same and a use of the same.


BACKGROUND ART

As a therapeutic agent for hyperlipemia, several compounds have been already put into practical use. In particular, it has been reported that an HMG-COA reductase inhibitor such as pravastatin or lovastatin exhibits a remarkable lowering activity of cholesterol and it can be said that the therapy of hypercholesterolemia has been rapidly progressing since the development of such medicines. However, such medicines could not lower a triglyceride level in blood.
On the other hand, as the medicines to lower both a cholesterol level and a triglyceride level, there have been put into practical use clofibrate type medicines and pharmaceutical preparations of nicotinic acid; however, nicotinic acid may develop at a high frequency side-effects such as itching, feverish feeling, rash etc., while clofibrate type medicines have presented the problem of side-effects such as easier formation of gallstone, muscular disorders, hepatic dysfunctions, gastrointestinal disorders, etc. There has been also presented the problem of a considerably higher dose, a dose of niacin as a pharmaceutical preparation of nicotinic acid being 2-3 g and aluminum clofibrate being 1.5 g.


DISCLOSURE OF INVENTION

The subject of this invention is to provide a compound which can far more strongly lower both plasma cholesterol and plasma triglyceride levels as compared with the prior art medicines in order to accomplish the treatment and prevention of hyperlipemia effectively.
Since a greater part of cholesterol and triglyceride in plasma is synthesized in and secreted from liver, it is expectable that a substance capable of inhibiting the secretion of both cholesterol and triglyceride in hepatic cells would be a therapeutic agent for hyperlipemia which can lower both of plasma cholesterol and triglyceride levels. The present inventors have used Hep G2 cells as the model cell for hepatocytes and investigated metabolites produced by microorganisms seeking for the compound which may inhibit the secretion of both cholesterol and triglyceride, and, as a result, found out the active ingredients in a cultured broth of a certain bacteria, which are those compounds having a cyclic depsipeptide structure. These depsipeptides have been isolated and purified from the cultured broth and then proven that they are new compounds. As a result of further studies, it has been confirmed that these cyclic depsipeptides can inhibit the production of apolipoprotein B in hepatic cells or the like, which is the main constitutive protein of very low density lipoprotein (VLDL) regarded as the cause of arteriosclerosis, and can selectively inhibit the secretion of lipids without preventing the synthesis of other proteins such as albumin and others in hepatic cells, upon which this invention has been completed.
According to this invention, there is provided a cyclic depsipeptide represented by the following structural formula (I) ##STR2## (wherein n represents an integer of 5-15) and a pharmacologically acceptable salt thereof. Preferable are the compounds of the above formula wherein n is an integer of 6-12 and particularly preferable are those compounds wherein n is an integer of 7, 8, 9 or 10.
According to this invention, there is also provided a process for the production of such a cyclic depsipeptide which comprises cultivating a microorganism belonging to the genus of Bacillus and capable of producing the above-mentioned novel cyclic depsipeptide and recovering the cyclic depsipeptide from the cultured broth.
According to this invention, there is further provided a pharmaceutical composition which

REFERENCES:
patent: 4891220 (1990-01-01), Donzis
Peptide Chemistry 1994, Protein Research Foundation, No. 32.sup.nd, pp. 33-36, 1995, XP 000653596, Takeshi Ohshima, et al., "A New Endothelin Antagonist Lipopetide Isolated from the Strain of Bacillus subtilis".

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