Triantennary cluster glycosides, their preparation and use

Details Triantennary cluster glycosides, their preparation and use Triantennary cluster glycosides, their preparation and use

1995-05-04

1999-03-23

Peselev, Elli

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Carbohydrate doai

536 41, 536 172, 536 173, A61K 3170, C07H 1500

Patent

active

058859683

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to triantennary cluster glycosides, i.e., compounds which contain a cluster of three sugar groups and thereby can be recognized by certain receptors present in the human or animal liver.
Such triantennary cluster glycosides can be used for different purposes, for instance, if the triantennary cluster glycoside comprises a cholesterol residue or an alternative lipophilic group, for the in vivo delivery of lipoproteins and lipid vesicles from the blood to the liver within the framework of a therapeutic treatment of hyperlipidemia.


PRIOR ART

Ways of piloting lipoproteins and lipid vesicles to the liver via a suitable route have been searched for before, on the one hand to create a transport vehicle that directs drugs specifically to the liver and, on the other hand, to remove the atherogenic low density lipoprotein (LDL) from the bloodstream.
Glycolipids have been developed in order to induce liver uptake of lipid vesicles or lipoproteins via the asialoglycoprotein receptor on the parenchymal cell of the liver, such as cholesteryl glycosides (refs. 1-4) lactosyl cerebrosides and gangliosides (refs. 5-9) and chemically modified phospholipids (refs. 10-11).
However, when associated to lipoproteins/liposomes, these known compounds will display preference for uptake by the likewise galactose recognizing fucose/galactose receptor on hepatic Kupffer cells, which hampers a potential application of these compounds in drug-targeting. The fucose/galactose receptor binds sugars, glycoproteins and particles, exposing a high density of terminal galactose groups (ref.22). Probably, high affinity binding does not essentially require di-, tri- or tetraantennarity of the glycoside.
The afore-mentioned glycolipids contain a ligand which is recognized by the asialoglycoprotein receptor on the parenchymal cell of the liver. This receptor represents an uptake system of high capacity and a unique localization on the parenchymal cell of the liver. The receptor can recognize sugars and glycoproteins with terminal galactose groups, it having a clear preference for oligoantennary sugars.
The above-mentioned compounds further comprise a structure which provides for an association of the ligand to lipid vesicles or lipoproteins. To that end, the substances are provided with a lipid part which associates spontaneously with lipid vesicles or lipoproteins.
A disadvantage of these known glycolipids is inter alia that they are not water-soluble, which makes the in vivo use of these substances difficult.
For this reason research has been conducted on a water-soluble clustered galactosolipid: tris-gal-chol of formula 22 (refs. 12-15, and 26). These investigations demonstrated that this compound is capable of irreversibly removing cholesterol from the bloodstream and inducing cholesterol uptake by the liver.
However, various disadvantages are associated with the use of tris-gal-chol as a hypolipidemic agent. In the first place, its potency is low: high doses of tris-gal-chol are necessary for a significant reduction of the LDL level in the bloodstream (ref. 15). Moreover, after injection of tris-gal-chol, the LDL is not removed via the asialoglycoprotein receptors on hepatocytes but via the Fuc/Gal receptors on hepatic Kupffer cells. Removal by the first-mentioned type of cells is much to be preferred to a removal by the last-mentioned type of cells, since only hepatocytes are capable of converting cholesterol from LDL into bile acids and secreting them in the bile.
It can be argued that both the low specificity for targeting (lipo)proteins to the hepatic parenchymal cell and the low hypocholesterolemic potency of tris-gal-chol were linked up with the low specificity and affinity of the glycoside for the asialoglycoprotein receptor. A further optimization of cluster glycoside from tris-gal-chol with respect to the affinity and specificity for the asialoglycoprotein receptor were required.
Previously, Lee et al. had reported a study of the prerequisites of high affinity recognition by the asialog

REFERENCES:
patent: 4751219 (1988-06-01), Kemper

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