MX2011009741A - Methionine-derived peptidomimetic compounds and use thereof for the protection of skin-cells mitochondria. - Google Patents

Abstract

The present invention discloses a methionine-derived peptidomimetic of formula (II) wherein R is XC (O)-NH-, wherein X is a C1-C8 alkyl or alkyloxy. It also relates to a pharmaceutical composition for topical administration. Said compound is useful against skin disorders associated with mitochondrial dysfunction.

Description

PEPTIDOMIMETICS DERIVED FROM METHIONINE AND ITS USE IN THE PROTECTION OF MITOCHONDRIA OF CUTANEOUS CELLS The invention concerns a selection of peptidomimetics derived from the amino acid methionine, and its use as a protective agent of the mitochondria of skin cells. The invention also concerns compositions intended to prevent or fight against skin disorders associated with mitochondrial dysfunction.

Cytoplasmic organelle present in plant and animal cells, the mitochondria plays a key role for the latter. Indeed, mitochondria are presented as the "energy centers of our cells", with the production and storage of adenosine triphosphate (ATP), the universal energy component necessary for the functioning of every eukaryotic cell.

The oxidizer, necessary for such production via a set of oxidation-reduction chemical reactions commonly called "mitochondrial respiratory chain", is oxygen. Oxygen is therefore indispensable to cellular functioning, but paradoxically, it is also the initial and parallel source of reactive species called "reactive oxygen-derived species" (ROS) potentially toxic to the cell's biochemical macromolecules. (DNA, proteins, lipids, etc.).

To neutralize this formation of ROS, every cell naturally develops antioxidant defense systems, enzymatic or not, requiring a little energy for its commissioning, first of all effectively this ATP produced in the mitochondrial respiratory chain (Singh K., FE S Yeast Res., 2004, vol.5, pp.127-132). Now, when an imbalance between production and elimination of ROS by the intracellular defense systems occurs in the margin of quantities that become too intense, the resulting oxidative stress then progressively engenders a decrease in mitochondrial functions, expressed especially by a deregulation of the flow of electrons energy producer and the formation of ROS inside the mitochondria, called "intra-mitochondrial ROS" (Jones DP, Chemico Biological Comm., 2006, vol.163, pp.38-53). Such imbalance and deficit of energy at the level of the cell compromise the ability of the cell to adapt to the physiological stresses to which it is exposed, contributing in fine to the phenomenon of cell aging (Trifunovic A., et al., J. of Internal Medicine , vol.263, pp.167-178). It is also admitted that these deregulations of mitochondrial origin are clearly involved in the genesis of a wide spectrum of pathologies or tissue disorders (Barlow-Stewart K., The Australasian Genetics Ressource Book, 2007, pp.1-3, and references cited) .

Source of intracellular ROS, the mitochondria is its main target. Consequently, and in order to preserve as much as possible the functional and / or structural integrity of all mitochondria, one of the current concerns of many researchers is to try to reduce the oxidative metabolism of mitochondrial origin and to stimulate or protect the functions of the mitochondria.

In the state of the art shown in recent years with the same objectives, the strategies and systems retained have often been divided between: - the selection of powerful antioxidants carrying one or more thiol or phenol motifs, and found in the natural state in the animal or vegetable kingdoms, such as the thioctic acid, better known as alpha-lipoic acid, with proven benefits against mitochondrial aging (Palaniappan AR et al., Neurochem. Res., 2007, vol .32, pp.1552-8), or also Ergotionine, which is a thiourea derivative announced to protect the membranes of mammalian mitochondria (US patent 6479533) , the use of certain conventional antioxidant molecules or proteins, modified however by the addition / insertion of groups or sequences (hydrophobic cation, etc.) with high affinity for the mitochondria and for greater accumulation therein (Kagan VE et al., Adv. Drug Delivery Rev., 2009, vol.61, pp.1375-85), the development of small peptides announced "cell-permeable" alternating aromatic and basic amino acid residues, due to their ability to penetrate the inner mitochondrial membrane and then squeeze the properties of cyto- and mitoprotection (Szeto HH, Antioxidants &Redox Signaling, 2008 , vol.3, pp.1-15).

The present invention has been developed in the same context of identification of new products or new preparations to respond to the general request to "improve the functioning of mitochondria" (B. Lacroix, Nutranews, April 2008), for cosmetic applications and / or dermatological due to the administration of these products or preparations mainly by cutaneous topical route and with the following concomitant objectives: - preserve / restore an effective metabolic activity of the mitochondria of the skin cells when the latter are physiologically affected; present an acceptable bioavailability in the deep layers of the skin. On the one hand, it is accepted that this is an essential prerequisite for in vivo protection of the mitochondria of skin cells. On the other hand, it is useful to avoid too early metabolization in the upper layers of the skin before being able to act on the epidermal and dermal cells; oppose the deleterious effects of reactive species derived from oxygen with respect to these same cells, both the ROS of intra-mitochondrial formation that of extracellular origin (UV rays, contamination, oxidant environmental toxins, etc.).

To achieve these ends, the applicant has been interested in the thioether compounds to which are attributed a capacity to deactivate ("quenching") various excited states of oxygen, 02 ° "and x02 for example (Cohen SG and L., J Am. Chem. Soc, 1975, vol.97, pp.5633-5634 and cited references).

The sulfonated alpha-amino acid methionine in which the sulfur atom participates in the same thioether function (S-CH3) has been more particularly interested, despite certain characteristics linked to methionine contrary to the intended purposes: recognized smell of the derivatives thio-organic compounds with a cosmetic / dermatological use, low penetrating power in the skin, and above all the exposition of intra-mitochondrial ROS and oxidative damages of the mitochondrial DNA generated by a dietary supplementation in methionine (Caro P. and col., Rev. Esp. Geriatr Gerontol., 2009, vol.44, pp.194-199, Sanz A. et al., FASEB J., 2006, vol.20, pp.1064-1073). In addition, it is presumable for peptides of the oligomethionine type (dimethionine, trimethionine, etc.) a high sensitivity with respect to the cutaneous proteases.

It is for that reason in definitive that the applicant oriented towards the end of the investigation towards the synthesis of peptidomimetics derived from methionine.

Thus, at the end of a structure-activity research, the applicant's choice has been directed to a limited panel of original compounds derived from methionine, with respect to its advantageous response to the combination of above-mentioned criteria and without the disadvantages attributed to the methionine or oligomethionines, advantageous response illustrated by: - an excellent ability to maintain the metabolic activity of skin cells exposed to stress, reflected by a preservation of ATP production levels [cf. test 1 below]; - a completely favorable cutaneous absorption, also going beyond the stratum corneum, revealed by obtaining a logarithmic value of its permeability coefficient ("Log Kp") comparable to that achieved for permeating compounds such as caffeine [cf. test 2 below]; - a capacity to reduce mitochondrial oxidative stress, as well as an ability to modulate the mitochondrial mass (called "mitochondrial biogenesis") resulting in response to the same stress conditions [cf. test 3 below]; - a high cytoprotection, expressed in particular on a cell line of fibroblasts "V79" [cf. test 4 below] whose characteristic is to be sensitive to hydrogen peroxide H202 at the origin of disorders in the mitochondrial respiratory chain (Tatsumi T. et al., Basic Res. Cardiol., 1993, vol.88, pp. 199-211 ); - a strong antioxidant profile translated by a capacity to sequester oxidizing species known to alter the mitochondria (hydroxyl radical 0H °, peroxinitrites 0N00", oxygen singulet 102), similar to that of reference antioxidants such as ascorbic acid or Trolox ™ [see test 5 and 6 below]; - a slight odor by these methionine derivatives.

The invention therefore has as its first object a family of peptidomimetics derived from methionine, characterized in what is represented by the following general formula (I): R = X-C (0) -NH- with X = alkyl or alkyloxy (q-Cg); R '= H OR R '= -C (0) -OX with X = alkyl (q -Cg); R = H Following a preferred embodiment of the invention, formula (I) is then limited to formula (II) wherein radical R 'is exclusively a hydrogen atom and R is a radical where X is of the alkyl or alkyloxy type with a chain linear or branched hydrocarbon including one to four carbon atoms (C1-C4): More advantageously, X in the above formula (II) is of the alkyl type with a straight or branched hydrocarbon chain including one to four carbon atoms (C1-C4).

By way of non-limiting examples of compounds of formula (II), the following compounds can be especially mentioned: - N-acetyl- (DL) -methionyl-4- (methylthio) propylamine - N-propionyl- (DL) - methionyl - - (methylthio) propylamine - N-pentanoyl- (DL) - methionyl -4 - (methylthio) propylamine - N-t-butyloxy- (DL) -methionyl-4- (methylthio) pyrilamine Following a still more advantageous embodiment of the invention, the above formulas (I) and (II) indicate in particular the compound N-acetyl- (DL) -methionyl-4- (methylthio) propylamine (R = CH 3 -C (0) -NH- and R '= H).

According to a second aspect, the invention also extends to a composition, preferably for cosmetic or dermatological use, intended to prevent or fight against skin disorders physiologically associated with a mitochondrial dysfunction, including, in association with any skin compatible adjuvant, As the main active ingredient, a peptidomimetic derivative of methionine of general formula (I) as previously defined.

In the context of the present invention, "active ingredient" is understood as an active substance capable of limiting the functional or structural alterations of the mitochondria of skin cells subjected to physical-chemical or environmental stress, by means of a protection process reinforced mitochondria and / or the stimulation of certain essential functions, such as cellular energy metabolism.

In particular, the aforementioned composition is intended to protect the skin from a stress induced by U.V. (UV-induced stress), and the methionine derivative is of formula (II), particularly is the compound N-acetyl- (DL) -methionyl-4- (methylthio) pyrilamine.

Advantageously, the amount of the said derivative of general formula (I) in the composition is comprised between 0.1% and 10% by weight with respect to the total weight of the composition, preferably between 0.3% and 3% by weight .

The compositions according to the invention, preferably for cosmetic or dermatological use, are adapted to topical cutaneous administration, presented under all the forms normally used for such administration. Advantageously, they can be in the form of a powder, an emulsion, a micro-emulsion, a nano-emulsion, a suspension, a lotion, a cream, an aqueous or hydro-alcoholic gel, a foam, a serum, a solution or a dispersion for aerosol, or a dispersion of lipid vesicles.

They can also be formulated for oral administration (administration per os), in the form of, for example, tablets, capsules, ampoules, syrup, drops.

Mention may be made, as an example of a physiologically compatible skin aid, of a compound selected from oils, waxes, silicone elastomers, surfactants, co-surfactants, thickeners and / or gelling agents, humectants, emollients, organic filters, inorganic filters, filter "boosters" and photostabilising agents, preservatives, dyes, fillers, nacres, mattifying agents, tensile agents, sequestrants, perfumes and their mixtures.

Of such examples, which may be present in the composition at a concentration of the order of 0.01% to 20% with respect to the total weight of the composition, they are cited especially in the dictionary "International Cosmetic Ingredient Dictionary and Handbook" (13a ( thirteenth) Edition, 2010), published by the "Personnal Care Product Council (PCPC, ex-CTFA)" of the American cosmetic association, and can be (without this list is limiting): silicone oils, synthetic oils or origin natural, linear or branched hydrocarbons, synthetic esters and ethers, hydrocarbon waxes, emulsifying surfactants, linear or branched fatty alcohol, crosslinked homo- and copolymers, gums, cellulose derivatives, alginates, polyols, sugars, glycosaminoglycans and other amino acids, mineral fillers or organic, vegetable proteins, polysaccharides, and their mixtures.

The compositions according to the invention can also include additional active ingredients, in such a way that the effect linked to the compositions according to the invention is not altered by the planned addition, especially at least one active selected from the agents that stimulate the production of growth factors, anti-glycation or deglyping agents, agents that increase collagen synthesis or prevent its degradation, agents that increase the synthesis of elastin or prevent its degradation, agents that increase the synthesis of glycosaminoglycans or proteoglycans or prevent their degradation, the agents that increase the proliferation or differentiation of the keratinocytes, the agents that increase the proliferation of the fibroblasts, the depigmenting agents, anti-pigmenting or pro-pigmenting, the anti-oxidant or anti-radical or anti-contaminating agents, the stimulating agents hydration and / or protect the barrier function of the skin, the agents that increase the synthesis of epidermal lipids, the agents that stimulate lipolysis, inhibiting lipogenesis and / or inhibiting the differentiation of adipocytes, draining or detoxifying agents, anti-inflammatory agents, penetration-accelerating agents , desquamating agents, relieving and / or anti-irritant agents, astringent agents, soothing agents, agents that act on microcirculation, agents that act on the metabolism of cells, and their combinations, and without This list is limitative.

Examples of such additional actives may be present in the composition at a concentration of the order of 0.001% to about 10% relative to the total weight of the composition, and may be chosen from plant extracts, silicon derivatives, extracts of yeast and algae, vegetable protein hydrolysates, acylated or non-acylated oligopeptides, coffee extracts, carcinin and its derivatives, carnosine and its derivatives, N-acetylcysteine and its derivatives, water-soluble vitamins such as vitamins Bl , B2, B3, B6, B12, C, H, fat-soluble vitamins such as vitamins A, D2, D3, E and carotene, urea and its derivatives, taurine and its derivatives, polyphenols, oligo- and polysaccharides , the lactic, glycolic, citric and salicylic acids and their ester or salts, and their mixtures.

Another object of the invention also concerns the use of a peptidomimetic derivative of methionine as a cosmetic agent intended to protect and / or stimulate the mitochondria of skin cells, the said derivative is of general formula (III) below R = XC (0) -NH- with X = alkyl or alkyloxy (q-Cg); R '= H 0 -C (0) R "with R" = 0alkyl (CrC 4), NH 2 Following an advantageous embodiment of The invention is aimed at preventing or combating the cutaneous signs of aging, with the aforementioned use of the said derivative, preferably against the cutaneous signs of photo-induced aging, in particular against the damages caused to the skin by UV rays.

A final object of the invention concerns a peptidomimetic derivative of methionine for use in a dermatological composition for the treatment of skin signs of aging, preferably against damage caused to the skin by UV radiation, the said derivative is of general formula (III) following: R = X-C (0) -NH- with X = alkyl or alkyloxy (q-C8); R '= H O -C -C (0) R "with R" = O-alkyl (CrC4), NH2 By way of non-limiting examples of compounds of formula (III), the following compounds may be mentioned in particular: - N-acetyl- (DL) -methionyl-4- (methylthio) pyrilamine - N-propionyl- (DL) - methionyl-4- (methylthio) pyrilamine - N-pentanoyl- (DL) - methionyl-4- (methylthio) propylamine - N butyloxy- (DL) - methionyl-4- (methylthio) pyrilamine - N-4- (methylthio) -butyryl-L-methionine methyl ester - N-acetyl- (DL) -methionyl-methionine ethyl ester In the latter two objects of the invention as mentioned above, a derivative of general formula (III) is preferably retained such as R is limited to a radical where X is of the alkyl type including from one to four carbon atoms (C1- C4) and R1 is exclusively a hydrogen atom.

Preferably still, the compound N-acetyl- (DL) -methionyl-4 - (methylthio) -propylamine is selected in a particular manner.

Example 1 : By way of illustration, examples of composition formulation according to the invention, containing a derivative of general formula (I) mentioned above, are mentioned below: Formula A (cream) N-acetyl- (DL) -methionyl-4- (methylthio) propylamine 1% Hydrogenated polyisobutene 7% Isobutyl myristate 3% Cetyl Palmitate 7% Ethylene glycol monostearate 5% Laurato de sorbitan 2% Polysorbate 20 2% Carbomer (acrylate / acrylamide copolymer &mineral oil) 0.3% 0.5% phenoxyethanol 0.2% sodium benzoate Water csp 100% Formula B (gel) N-t-butyloxy- (DL) -methionyl-4- (methylthio) propylamine 3% Carbomer (acrylate / acrylamide copolymer &mineral oil) 1.5% 0.2% sodium benzoate Sorbic acid 1% 1, 3 -butanediol 10% Glycerin 5% Caustic soda 0.13% 0.9% phenoxyethanol Water csp 100% Formula C (capsule, per os administration) N-acetyl- (DL) -methionyl-4- (methylthio) propylamine (200 mg powder / capsule) 0 N-4- (methylthio) -butyryl-L-methionine methyl ester (200 mg powder / capsule) Excipients csp 1 capsule in gelatin: microcrystalline cellulose, magnesium stearate.

Example 2: The invention is illustrated below, purely by way of indication, by the following higher evoked tests in the description of the invention (tests 1 to 6). It is also to be noted that in vivo studies on man are being done and that the first results are equally capable of illustrating the use of certain methionine-derived peptidomimetics for the purposes of the present invention.

Test 1: demonstration of the capacity of peptidomimetics derived from methionine to restore the levels of cellular ATP on the target cells of a stress (H2O2): The experimental study was carried out on a cell line of fibroblasts of type "V79" and seeded in a plate of 96 wells at the rate of 5000 cells per well in 100 μ? of culture medium (containing 10% fetal calf serum). This is then substituted in each of the wells by 100 μ? of medium including the peptidomimetics according to the invention, at the concentration of 7.5 m or 10 mM. After 2 hours of incubation, the medium is withdrawn over the whole of the wells, then the cells are subjected to a state of stress with the addition of a medium containing 50 μ? of hydrogen peroxide H202 (4 ppm). After 8 new hours of incubation, the average concentration in ATP is measured by luminance in the presence of Luciferin (kit "ATPlite lstep") and by means of a standard curve prepared from highly purified ATP.

The results, expressed as the mean value obtained from three independent experiments, are presented in Table 1 below, as compared to a control.

Table 1 The massive drop in the amount of ATP observed for the control is very widely prevented in the presence of the compounds according to the invention, thus demonstrating its ability to restore ATP production within cells subjected to stress.

Test 2: study of percutaneous absorption of peptidpmimetics derived from methionine on human skin explants: The values of the permeability coefficient (Kp) have been obtained on a previously frozen human skin obtained from an abdominalplasty, in accordance with the protocol described in guideline n ° 428 of the OECD on the conduct of skin absorption studies.

Experimentally, the skin explants have been placed on a passive diffusion Frantz cell, piloted by the "MicroettePlus Hanson Research" system, and the products studied are applied in non-occlusive mode. After placing the skin on the cells, 500 μ? of the peptide mimetic according to the invention (1% solution) have been deposited in each of the cells and for a total contact time of 24 hours. At the end of these, the remaining product is removed and the surface of the skin rinsed for extraction and measurement of the quantity absorbed, then for the determination of the permeability coefficient expressed in logarithmic form (Log Kp).

The results are gathered in table 2 below.

Table 2 **: Mitragotri S., J. Controlled Reléase, (2003), vol.86, pp.69-92 ***: according to the predicate logger "ChemDraw ultra version 11.0", server: CambridgeSoft Ltd The coefficient of permeability obtained by the compounds according to the invention is comparable to that obtained for caffeine, recognized permeant trans-stratum corneum.

Test 3: demonstration of the protective effect of the compound N-acetyl- (DL) -methionyl-4- (methylthio) propylamine on mitochondrial oxidative stress and on mitochondrial biogenesis; Principles: measurements of mitochondrial intracellular oxidative stress and detection of mitochondrial biogenesis were performed by flow cytometry using the following fluorochrome markers: - the red fluorescent probe "MitoSOX ™ Red" hereinafter designated "MitoSOX (detection α = 580 nm, supplier: Invitrogen) allows to specifically detect the superoxide anion 02 °" present in the mitochondria (due to its strong affinity for this ), - the green fluorescent probe "MitoTracker® Green FM", hereinafter referred to as "Mitogreen" (detection at? 516 nm, supplier: Invitrogen) allows to quantify the mitochondrial mass (or relative name of mitochondria per cell).

Experimentally, the tests were performed on a hamster adherent fibroblast line "V79", maintained by cocking in a complete culture medium "EMEM" (with 10% fetal calf serum) in humid atmosphere at 37 ° C and with 5 % of C02. The V79 cells are seeded and then incubated 24 hours in the plates 6 wells at 2.5.105 cells per well in 3 ml of the same culture medium, then they are subjected to a state of stress for lh30 by the addition of a half qu contains hydrogen peroxide H202 (15 ppm).

After trypsinization, the cells are incubated at 37 ° C for 15 minutes in 1 ml of complete culture medium "EMEM" and contains the above markers "MitoSOX", at the final concentration of 5 μ ?, and "Mitogreen" (a the final concentration of 200 nM) for respective detection: - of mitochondrial oxidative stress (expressed in% of positive cells), - and of the mitochondrial mass per cell (expressed in% of MFI ("Mean Fluorescence Intensity") with respect to the control).

The results, which meet the average values obtained from four independent experiments, are presented in tables 3a and 3b below, in comparison with those obtained with the N-acetyl-cysteine chosen as the protective agent of reference to the concentration of 5 mM.

Table 3a Table 3b In both cases, the results underline for the compound N-acetyl- (DL) -methionyl-4- (methylthio) pyrilamine a capacity to reduce the effect of intramitochondrial stress.

Test 4: demonstration of the cytoprotective effect of the peptidomimetics N-acetyl- (DL) -methionyl-4- (methylthio) -propylamine and N-butyloxy- (DL) -methionyl-4- (methylthio) -propylamine: The experimental study was carried out on a hamster adherent fibroblasts line "V79", maintained in a humid atmosphere at 37 ° C and with 5% C02, then plated in 96 wells at a rate of 0.5.104 cells per well. 0.2 ml of the complete culture medium "EMEM" (with 10% fetal calf serum). The cells are then subjected to a toxic stress state for 24 hours by replacing the culture medium with a medium containing hydrogen peroxide H202 (4 ppm), medium to which the compound according to the invention is simultaneously added.

After removal of the medium, the cell viability of the fibroblasts is measured via the "MTT method" or 3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide (solution at 500 9 /? ? 1) and by spectrophotometry (absorbance at 540 nm).

The results, which reunite the average values obtained from three independent experiments, are presented in table 4 below, again compared with those obtained with the 5 mM N-acetyl-cysteine chosen as reference cytoprotector (total restoration of a cell viability).

Table 4 The results of Table 4 underline, for the compounds according to the invention, a dose-dependent cell viability and a capacity to protect the cells from a cytotoxic stress.

Test 5: demonstration of the antioxidant effect of the peptidomimetics N-acetyl- (DL) -methionyl-4- (methylthio) -propylamine and N-propionyl- (DL) -methionyl-4- (methylthio) -propylamine with respect to the hydroxyl radical The method, described by Rehman A. and coll. (British J. Pharmacol. (1997), vol.122, pp. 1702-1706) is used for the determination of the rate of sequestration of the hydroxyl radical [Ks (0H °)], the peptidomimetic according to the invention is compared to two reference antioxidants, mannitol and ascorbic acid (vitamin C).

Experimentally, the test substance is dissolved in a buffered medium at pH 7.4 to which a 0H ° generating medium (ascorbate / iron / EDTA system) is added in the presence of deoxyribose. After one hour of incubation at 37 ° C, the reaction is stopped by means of trichloroacetic acid. After colorimetric revelation with thiobarbituric acid, the absorbance is measured at 532 nm for different concentrations, then the Ks (OH °) relative to each one of the substances is calculated.

The results are shown in table 5 below.

Table 5 **: Cabelli D.E., J. Phys. Chem. (1983), vol.87, pp.1809-1812] ***: Rehman A., British J. Pharmacol. (1997), vol.122, pp.1702-1706)] The results, expressed as average values obtained from three independent experiments, underline for the peptidomimetics according to the invention a capacity to sequester the hydroxyl radical (OH) much more efficiently than that of mannitol, and a little lower in comparison with that of the acid ascorbic Test 6: demonstration of the antioxidant effect of the compound N-acetyl- (DL) -methionyl -4 - (methylthio) propylamine with respect to peroxynitrites The method, called "Pyrogallol Red (PR) M bleaching test, described by Nath VB et al (BBRC (2001), vol 285, pp. 262-266) is used for the determination of the inhibition of Oxidation of pyrogallol red (PR) by peroxynitrite ions (ONOCf), the N-acetyl- (DL) -methionyl-4- (methylthio) propylamine compound according to the invention being compared to a reference antioxidant, namely the "Trolox ™ "or 6-hydroxy -2, 5,7, 8-tetramethylchroman-2-Carboxylic acid, water-soluble equivalent of vitamin E.

Experimentally, in a 96 well plate, the test substance dissolved in a buffered medium at pH 7.0 to which 50 μ? of PR and 25 μ? of ONOO peroxynitrite ions (in solution in 0.1 M NaOH) After 5 minutes, the absorbance is measured by spectrophotometry at 540 nm, then the IC50 (inhibitory concentration of 50%) relative to each of the substances is calculated. The results are shown in table 6 below.

Table 6 Less active than the reference antioxidant, the inhibition of the oxidation of the PR by the peroxinitrites is nevertheless clearly observed for the compound according to the invention.

Claims (10)

1. Peptidomimetic derivative of methionine, characterized in what is represented by the following general formula (II):

2. Peptidomimetic according to claim 1, characterized in that it is N-acetyl- (DL) -methionyl -4 - (methylthio) ropilamine.

3. Composition intended to prevent or fight against skin disorders associated with mitochondrial dysfunction, characterized in that it comprises a peptidomimetic derivative of the methionine of formula (II) below: R = X-C (0) -NH- with X = alkyl or alkyloxy (q-C8); R '= H

4. Compositions according to claim 3, characterized characterized in that the said peptidomimetic is N-acetyl- (DL) -methionyl-4- (methylthio) propylamine.

5. Composition according to any one of claims 3 to 4, characterized in that the amount of said peptidomimetic is comprised between 0.1% and 10% by weight with respect to the total weight of the composition.

6. Composition according to any one of claims 3 to 5, characterized in that it is adapted to topical cutaneous administration, presented in the form of a powder, an emulsion, a micro-emulsion, a nano-emulsion, a suspension, a lotion, a cream, an aqueous or hydro-alcoholic gel, a foam, a serum, a solution or an aerosol dispersion, or a dispersion of lipid vesicles.

. Compositions according to any of claims 3 to 6, characterized in that it includes additional active ingredients chosen from agents that stimulate the production of growth factors, anti-glycation agents or desgliants, agents that increase the synthesis of collagen or prevent its damage , of agents that increase the synthesis of elastin or prevent its damage, of agents that increase the synthesis of glycosaminoglycans or of proteoglycans or prevent their damage, of agents that increase the proliferation or differentiation of keratinocytes, of agents that increase the proliferation of fibroblasts, depigmenting, anti-pigmenting or pro-pigmenting agents, anti-oxidants or anti-radical or anti-contamination agents, agents that stimulate hydration and / or protect the barrier function of the skin, agents that increase the synthesis of epidermal lipids, agents that stimulate lipolysis, inhibiting lipogenesis and / or in hybing the differentiation of adipocytes, draining or detoxifying agents, anti-inflammatory agents, penetration-accelerating agents, desquamating agents, relieving agents and / or anti-irritants, astringent agents, agents that act on the metabolism of cells , and its mixtures.

8. Composition according to any one of claims 3 to 7, characterized in that it is intended to protect the skin from a stress "UV-induces."

9. Use of a peptidomimetic derivative of methionine as a cosmetic agent intended to protect and / or stimulate the mitochondria of skin cells, the said peptidomimetic is of general formula (III) below: R = X-C (0) -NH- with X = alkyl or alkyloxy (q-C8); R '= H O -C -C (0) R "with R" = O-alkyl (CrC4), NH2

10. Peptidomimetic derivative of methionine for use in a dermatological composition for the treatment of cutaneous signs of aging, the said derivative is of general formula (III) below: R = X-C (0) -NH- with X = alkyl or alkyloxy (q-C8); R '= H O -C -C (0) R "with R" = O-alkyl (C1-C4), NH2