Inhibitors of melanocyte tyrosinase as topical skin lighteners

a technology of melanocyte tyrosinase and topical skin lighteners, which is applied in the field of inhibitors of melanocyte tyrosinase, can solve the problems of hyperpigmentation lesions or skin regions, compound is not an effective inhibitor of mammalian enzymes, and is difficult to achieve in a large proportion of subjects, so as to prevent oxidative decomposition of product formulations and protect skin

Inactive Publication Date: 2005-07-14
MEDIQUEST THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0015] An additional object of the invention is to provide antioxidant compositions that protect skin from oxidative damage, and / or to prevent oxidative decomposition of product formulations.

Problems solved by technology

However, acute or persistent UVB exposure can result in the formation of hyperpigmented lesions or regions of skin, including malignant melanoma skin cancer.
[17, 18, 20] Although it would be desirable to restore lost pigmentation in vitiligo-affected skin with topical therapies, this has proven to be quite difficult to accomplish in a high proportion of subjects.
Although it has been repeatedly asserted in the dermatologic literature for many years, without substantiation, that HQ is an inhibitor of tyrosinase, this compound is not an effective inhibitor of the mammalian enzyme [5, 6, 25].
MG has not been developed as a commercially available topical skin lightener product to date.
The compounds are various benzimidazolethiols, but have not been developed as commercially available topical skin lightener products to date.

Method used

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  • Inhibitors of melanocyte tyrosinase as topical skin lighteners
  • Inhibitors of melanocyte tyrosinase as topical skin lighteners
  • Inhibitors of melanocyte tyrosinase as topical skin lighteners

Examples

Experimental program
Comparison scheme
Effect test

example 1

Benzoimidazolethiols

[0385] A first class of compounds based upon the template compound benzimidazolethiol (lower left structure) were tested for tyrosinase inhibition, cell culture pigment inhibition, and toxicity, by methods described in Curto, E. V., et al. (1999) [25]. Results of the tests are given in Table 1.

TABLE 1ID #R1R2R3R5R6REPTελmax138NHSHNHHC0.25——14300300140NHSHNCH3HC0.122.4>10006300305084NHSHNOCH3HC0.071.6>100010000310040SSHNHHC8——091SSHNHOCH2CH3C>1000>1000>1000205NH═SN(CO)CH3HHC0.58.335098NH═SeNHHHC0.814132135NH═SNHHHN4256>1000

*Inhibition [μM] as measured in three assays. Here “E” is the concentration of compound that produces 50% pigment inhibition in the cell-free mammalian-enzyme assay system. “P” is for the concentration of compound that produces 50% inhibition in the mammalian-melanocyte-culture pigment assay system. “T” is the concentration of compound that kills 50% of cells in the

# mammalian-melanocyte-culture toxicity assay system. The compound extinction...

example 2

Thiophenols

[0386] A second class of compounds based upon the template compound benzenethiol were tested for tyrosinase inhibition, cell culture pigment inhibition, and toxicity, by methods described in Curto, E. V., et al. (1999) [25]. Results of the tests are given in Table 2.

TABLE 2ID #R1R2R3R4R5EPTελmax099HHOCH3HH53852023000265102HHHSCH3H0.241151262300280083HHHNH(CO)CH3H19825424700265103HHOCH3OCH3H88>10004300250093HOCH3HHOCH35002002002700305148(CO)CH3HHNH(CO)CH3H500301253300255

*Inhibition [μM] as measured in three assays. Here “E” is the concentration of compound that produces 50% pigment inhibition in the cell-free mammalian-enzyme assay system. “P” is for the concentration of compound that produces 50% inhibition in the mammalian-melanocyte-culture pigment assay system. “T” is the concentration of compound that kills 50% of cells

# in the mammalian-melanocyte-culture toxicity assay system. The compound extinction coefficient is ε [OD / M × cm] at the wavelength of maximum abso...

example 3

Phenylthioureas

[0387] A third class of compounds based upon the template compound phenylthiourea (lower left structure) were tested for tyrosinase inhibition, cell culture pigment inhibition, and toxicity, by methods described in Curto, E. V., et al. (1999) [25]. Results of the tests are given in Table 3.

TABLE 3ID #R2R3R4R5REPTελmax033HHHHNH2212>1000181OCH3HHHNH2>1000>1000105HFHHNH21.521.78>100011000255104HOHHHNH248>1000131HCH3HHNH20.822.28>1000053HHOCH3HNH283060049HHNH(CS)NH2HNH24250>1000101HCH3HCH3NH2250125>1000054HHHHCH31616>1000

*Inhibition [μM] as measured in three assays. Here “E” is the concentration of compound that produces 50% pigment inhibition in the cell-free mammalian-enzyme assay system. “P” is for the concentration of compound that produces 50% inhibition in the mammalian-melanocyte-culture pigment assay system. “T” is the concentration of compound that kills 50% of cells in the

# mammalian-melanocyte-culture toxicity assay system. The compound extinction coefficie...

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Abstract

Methods and formulations are provided to reduce pigmentation in skin, using an array of compounds selected from benzimidazoles, phenylthioureas, phenyltiols, phenylamines, bi- and multicyclic phenols, thiopheneamines, and benzothiamides. The compounds preferably inhibit pigment systhesis in melanocytes through the tyrosinase pathway. The methods can be used for lightening skin, and for treating uneven skin complexions which result from hyperpigmentation-related medical conditions such as melasma, age spots, freckles, ochronosis, and lentigo. The compounds can be used medically or cosmetically.

Description

CROSS REFERENCE TO PRIOR APPLICATIONS [0001] This application is a continuation of U.S. Ser. No. 09 / 795,683, filed Feb. 28, 2001, now abandoned and further claims priority to U.S. provisional patent application No. 60 / 185,610, filed Feb. 29, 2000. This application incorporates the entire disclosure of U.S. Ser. No. 09 / 795,683 and 60 / 185,610 as if fully set forth herein.FIELD OF THE INVENTION [0002] The present invention relates to compounds and methods for inhibiting the activity of melanocyte tyrosinase in mammalian skin, in order to reduce the expression and production of skin pigmentation, and thereby lighten the color of mammalian skin. BACKGROUND OF THE INVENTION [0003] Melanogenesis is the process of production and subsequent distribution of melanin by melanocytes within the skin and hair follicles [1, 2]. Melanocytes have specialized lysosome-like organelles, termed melanosomes, which contain several enzymes that mediate the production of melanin. The copper-containing enzyme...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K8/41A61K8/46A61K8/49A61K31/095A61K31/136A61K31/145A61K31/167A61K31/17A61K31/24A61K31/36A61K31/381A61K31/404A61K31/4184A61K31/428A61P17/00A61Q19/02
CPCA61K8/4946A61K31/145A61K8/4986A61Q19/02A61K31/167A61K8/4973A61K31/381A61K31/428A61K31/4184A61K2800/782A61K8/4913A61K31/136A61K8/411A61K31/404A61K31/17A61K8/46A61K31/24A61K31/095A61K31/36A61K8/49A61P17/00
Inventor DOOLEY, THOMAS P.CURTO, ERNEST V.
Owner MEDIQUEST THERAPEUTICS INC
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