Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1994-03-31
1995-08-01
Tsang, Cecilia
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514467, 514641, 549369, 549372, 549453, 549454, 564191, 564193, 564271, 564276, A61K 31335, A61K 3113, C07D31906, C07D31700, C07C23300, C07C25100
Patent
active
054380731
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/FR92/009081, filed Oct. 1, 1992.
The present invention relates to compositions for topical use which are, in particular, useful in dermatology and/or in cosmetology, as well as to the use of new retinoids for preparing such compositions. It also relates to a new group of retinoid derivatives.
In effect, it is commonly accepted that retinol, or (ROL), is essential for vision, reproduction, growth and cell differentiation; on the other hand, retinoic acid (or RA) is involved only in the regulation and control or differentiation of cell growth (Wolf. G., Physio. Rev. 64, p. 873-937; 1984);
Retinoic acid is present in plasma at a level approximately 150 times lower than that of retinol (Deleenhefr et al., J. Lipid. Res., 23, p. 1362 to 1367, 1982).
In addition, retinoic acid is rapidly eliminated from the body, suggesting that this acid is formed from retinol, close to the site of its biological action. Retinoic acid may be formed by enzymatic oxidation in two steps. During this process, retinol is oxidized to retinal, which is subsequently oxidized to retinoic acid. These two steps require the presence of cofactor NAD. Recent studies have shown the presence of an enzyme system which is capable of converting retinol to retinoic acid in certain tissues of rodents, such as the kidney and liver of rats, or the skin of mice (Connor M. J. et al., Biochem J., 244, p. 489-492, 1987).
However, these studies have not elucidated the question of the specificity of the enzyme systems involved with respect to their substrates: all these tissues contain high levels of alcohol and aldehyde dehydrogenases, which are capable of non-specifically oxidizing a large number of alcohols and aldehydes, including retinol and retinal.
These studies have not shown whether the dehydrogenases involved in the oxydation of ROL.fwdarw.RA in the natural metabolism of the retinoids are different from those involved in the metabolism of alcohol.
The origin of the retinoic acid utilized in epidermal cells is still being debated at the present time.
One source may be the retinoic acid in the plasma; however, owing to the fact that it is rapidly metabolized and eliminated, it is probable that the retinoic acid is formed enzymatically from retinol at its site of action. However, the studies of the prior art have not been able to elucidate the exact nature of the enzyme system involved.
The mechanism of action of retinoic acid and of its analogues in the cell brings into play nuclear receptors belonging to the superfamily of thyroxosteroidal hormone receptors which act as retinoic acid-inducible factors for genomic transcription (Krust A. et al., Proc. Natl., Acad. Sci., U.S.A., 86, 5310-5314, 1989). However, the analogy between the mode of action of thyroxo-steroid hormones and that of retinoic acid is not complete. In effect, retinoic acid in tissues requires an intracellular transporter protein, or CRABP (Cellular Retinoic Acid-Binding Protein), which probably acts as a carrier for transporting its ligand from the cytoplasm to the nucleus.
Retinoic acid is the active metabolite of retinol in certain specific functions (cell differentiation), because retinoic acid is much more active than retinol in the control of cell differentiation, suggesting that the conversion of retinol to retinoic acid would be partly responsible for the activity attributed to retinol. This is one of the reasons why retinoic acid or its analogues have been selected as therapeutic agents.
Moreover, Creek et al., (J. Invest. Dermatol., 92, p. 283-289, 1989), have shown that retinol supplied to the extracellular medium was metabolized to (inactive) retinol esters by keratinoctes [sic] in culture. Ottonello S. et al., (J. Biol. Chem., 262, p. 3975-3981, 1987) have shown that the plasma membrane of the target cells of retinoids possessed an extremely active enzyme system, which was capable of esterifying retinol in order to deactivate it and store it in the membranes. As a result, there is every reason to think that entry of retinol into the cel
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Cousse Henri
Gall Yvon
Mouzin Gilbert
Saurat Jean-Hilaire
Siegenthaler Georges
Pierre Fabre Cosmetique
Tsang Cecilia
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