Peptide derivatives of alpha-MSH and their application

Details Peptide derivatives of alpha-MSH and their application Peptide derivatives of alpha-MSH and their application

1995-05-22

1998-11-03

Marschel, Ardin H.

Chemistry: natural resins or derivatives; peptides or proteins;

Natural resins or derivatives

530350, 514 1, 514 2, A01N 6100, A01N 3718, A61K 3800, C07K 100

Patent

active

058309942

DESCRIPTION:

BRIEF SUMMARY
The present invention has especially peptide derivatives of .alpha.-MSH ("Melanocyte Stimulating Hormone"), presented in Lipoyl-Peptide form.
.alpha.-MSH and its homologs have been the subject of numerous publications or even of therapeutic trials without this resulting in the production of a medicinal product.
The principal reason is the extreme ubiquitousness of .alpha.-MSH depending on the administered doses and the routes of administration.
Furthermore, the absence of a dose-effect relationship (which is the case for numerous peptide hormones) seriously complicates its therapeutic use.
The cell receptors for .alpha.-MSH and its homologs are of the G type and intracellular transduction occurs according to the cyclic AMP cycle. The activation of these cell receptors is essentially inversely proportional to the peptide hormone doses accepted by the structures of the membrane receptor.
The present invention is based on the search for peptide structures specifically orientated towards anti-allergic and anti-inflammatory activities on the one hand, and melanogenesis-activating activities on the other, excluding any other pharmacological effect, especially at the level of the central nervous system, as well as the peripheral nervous system.
More particularly, the present invention relates to a compound containing a peptide sequence comprising at least one sequence of 4 amino acids obtained from .alpha.-MSH, the amino acids being in natural or nonnatural form, the said sequence being conjugated with thioctic acid or a derivative of this acid, in the form of the corresponding salts, esters or amides.
The sequence of .alpha.-MSH is the following:
N-acetyl-Ser-Tyr-Ser- Met-Glu- His-Phe-Arg-Trp-Gly-Lys-Pro-Val-NH.sub.2 -
In this definition, as in the text that will follow, the amino acids may be in D, L or D,L form and the nonnatural forms of the amino acids correspond to derivatives, especially substituted derivatives.
Thioctic acid or .alpha.-lipoic acid may be in oxidized form: ##STR1## or in the form of a dihydrolipoic derivative: ##STR2##
Among the derivatives of this acid, the N-lysine derivative of the oxidized or dihydro form must be mentioned.
One of the principal objects of the present invention is the therapeutic application via the topical (cutaneous) route of the preceding derivatives.
These compounds are molecules capable of crossing the cutaneous barrier and of presenting the peptide fraction to the cell receptors, inducing a biological response of the dose/effect relationship type.
These low molecular weight peptides whose amino acid sequences have been modified, are linked in the form of salts, esters or amides to active biochemical groups, playing a vital role in the tricarboxylic cycle (at the level of the mitochondria in particular). These cofactors are lipoic or thioctic acids in oxidized or reduced form and their Lipoyl-Lysine derivatives, which are naturally linked by covalent bonding to the polypeptide chains of the cellular enzymatic system.
More specifically, the present invention relates to peptides of 4 to 6 amino acids linked in the form of Lipoyl-Peptides and of Lipoyl-Lysyl-Peptides with anti-allergic, anti-inflammatory and melanogenesis-activating activity.
The compounds according to the invention preferably have the peptide sequence containing at least the following sequence: phenylalanine, it being possible for the amino acids to be in D, L or D,L form, and in particular they may be compounds having the formula:
Lip is thioctic acid or one of its derivatives,
X is Glu, OH or NH2,
Y is
Phe is homoPhe or p-fluoroPhe, the amino acids being in D, L or D,L form.
The invention relates more particularly to the following compounds: esters or of amides.
In the formulae, the position of thioctic acid corresponds to the ester or amide derivative, the acid fraction of thioctic acid assuring the bonding.
The amino acid sequences mentioned above may be natural amino acid sequences or nonnatural amino acid sequences. Likewise, in some cases it is possible that some of these amino acids contain f

REFERENCES:
patent: 4647655 (1987-03-01), Axen et al.
patent: 5017368 (1991-05-01), Sugiyama et al.
Hasunuma, Chemical Abstracts, vol. 108: 26828Z p. 321 (1988).
Tuaillon et al., Journal of Immunology, vol. 148:445-450 (1992).
International Search Report dated Jan. 25, 1995 for parent PCT application WO95/08564.
French Search Report dated Jun. 17, 1994 for priority application FR 93 11281.

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