JP2024095850A - Hair growth agent or hair loss inhibitor containing GPR30 agonist compound G-1 - Google Patents

Abstract

[Problem] To provide medicines, quasi-drugs, cosmetics, reagents, etc., which have excellent hair growth or hair loss suppression effects.
[Solution] It has been revealed that the cell membrane receptor GPR30 is distributed in hair follicles, particularly in hair papilla cells, and furthermore, it has been found that the GPR30 selective agonist (±)-1-[(3aR,4S,9bS)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone promotes hair growth. That is, the present invention is a hair growth agent or hair loss inhibitor characterized by containing a compound represented by the following formula [1] or a pharma- ceutical acceptable salt thereof, or a solvate thereof.

[Selected Figure] Figure 1

Description

The present invention relates to a hair growth agent or hair loss inhibitor containing (±)-1-[(3aR,4S,9bS)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone.

There are various types of alopecia, including male pattern baldness, female pattern baldness, seborrheic alopecia, senile alopecia, diffuse alopecia, alopecia areata, telogen effluvium, hair loss associated with infectious diseases, and thinning hair without a clear name. While most of these conditions are not life-threatening, the presence or absence of body hair, especially in areas that are visible from the outside, such as the head, eyelashes, and eyebrows, greatly affects the appearance and has a significant impact on the patient's QOL.
As methods for improving or preventing these alopecia, there are various hair growth agents and hair loss inhibitors available as medicines, quasi-drugs, and cosmetics, but their effectiveness is not necessarily sufficient, and there is a demand for products with even better effects.
It is said that hair loss is likely to occur in women after menopause, after childbirth, during menopause, etc. These are the times when female hormones are significantly reduced, so it is believed that hair loss is caused by the reduction of female hormones, especially estrogen (follicular hormone), and it is easy to think that supplementing estradiol and other estrogens is effective in improving alopecia.Therefore, estradiol and its derivatives are used as hair growth ingredients (Patent Documents 1 and 2).
However, it has been revealed that when estradiol is administered to mice, rather than promoting hair growth, it significantly suppresses hair growth regardless of gender (Non-Patent Documents 1, 2, 3, 4). In addition, the effects of removing the ovaries, which are the main estrogen-producing organs, on hair growth have not yet been clarified as of 2022, with the effects differing depending on the age of the mice (Non-Patent Document 5). There are several reports of female hormones acting on hair follicles in humans, but there is no consensus on the effects, and there are mixed reports of both suppressing and promoting hair follicle growth (Non-Patent Documents 6, 7).
Thus, the effect of female hormones on hair follicles is still unclear. In addition to estrogen, many other hormones, such as progesterone, oxytocin, relaxin, thyroid hormone, and testosterone, fluctuate during the period when hair loss is likely to occur in women, and the fluctuations of these hormones are thought to affect hair growth in a comprehensive manner, making it difficult to consider the effect of estrogen separately from other hormones in these phenomena (Non-Patent Document 8).

H S Oh et al. Proc Natl Acad Sci U S A.1996;93(22):12525-30. S Chanda et al. Am J Physiol Endocrinol Metab.2000;278(2):E202-10. U Ohnemus et al. Endocrinology.2005;146(3):1214-25. S Moverare et al. J Invest Dermatol.2002;119(5):1053-8. S Togo et al. Med Mol Morphol.2022;55(3):210-26. S Kondo et al. Arch Dermatol Res.1990;282(7):442-5. F Conrad et al. J Invest Dermatol.2004;122(3):840-2. U Ohnemus et al. Endocr Rev.2006;27(6):677-706.

JP 2021-31438 A JP 2009-256267 A

The object of the present invention is to provide a hair growth agent and hair loss inhibitor that exhibits excellent hair growth effects.

The inventors believed that the complexity of the action of estrogen on hair follicles is due to the fact that each receptor responds in a different direction.
In recent years, cell membrane receptors for sex hormones have been identified, including G protein-coupled estrogen receptor 1 (G protein-coupled estrogen receptor 30).

After extensive research, the inventors have found that the cell membrane receptor GPR30 is distributed in hair follicles, particularly in hair papilla cells, and have further found that the GPR30 selective agonist (±)-1-[(3aR,4S,9bS)-4-(6-bromo-1,3-benzodioxol-5-yl)-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinolin-8-yl]-ethanone (a compound represented by formula [1] below; hereinafter also referred to as G-1) promotes hair growth. In other words, they have found that activating GPR30 can exert a hair growth effect, and that GPR30 agonists can be used as agents to inhibit hair growth and hair loss, which has led to the completion of the present invention.

That is, the present invention provides:
(1) The following formula [1]
[Chemical formula 1]

or a pharma- ceutical product thereof, or a solvate thereof.

The hair growth agent or hair loss inhibitor containing G-1 or a medicament acceptable salt thereof, or a solvate thereof, according to the present invention, has excellent hair growth and hair loss inhibitory effects, and thus has the effect of preventing and improving various types of alopecia.

1 shows the results of evaluating the hair growth promoting effect of G-1 in wild-type mice in Test Example 1. The values show the average hair growth scores for each group. 2 shows the results of evaluating the hair growth promoting effect of G-1 in GPR30-deficient (knockout) mice in Test Example 2. The values show the average hair growth scores for each group.

In the present invention, G-1 is also called GPR30 agonist-1, and is a compound represented by Cas No. 881639-98-1. G-1 does not act on other estrogen receptors such as ERα/β, but selectively acts on GPR30 to activate it. G-1 can be synthesized by known methods, and is available commercially from various reagent manufacturers such as Cayman Chemical Company. In addition, there is no problem in using its pharmacologic acceptable salt, or a solvate of G-1 free form or its pharmacologic acceptable salt, as long as the action on GPR30 is not lost.

Examples of pharma- ceutically acceptable salts of G-1 of the present invention include mineral acid salts with hydrochloric acid, phosphoric acid, sulfuric acid, etc.; sulfonate salts with methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, 10-camphorsulfonic acid, etc.; metal salts with aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc.; and addition salts of organic acids with oxalic acid, tartaric acid, citric acid, maleic acid, succinic acid, acetic acid, benzoic acid, mandelic acid, ascorbic acid, lactic acid, gluconic acid, malic acid, etc. In addition, the compound G-1 of the present invention or a pharma-ceutically acceptable salt thereof may also exist as various solvates such as ethanol and water. From the viewpoint of applicability as a medicine, the solvate is preferably a hydrate.

The compound G-1 of the present invention is a compound containing three asymmetric carbon atoms. The compound of the present invention may be only one optical isomer or a mixture of optical isomers in any ratio.

The present invention is expected to produce similar hair growth promoting and hair loss suppressing effects even with other GPR30 agonists. If there are concerns about the effect on ER, it is possible to use an ER antagonist (e.g., fulvestrant) in combination to specifically activate GPR30 and produce the desired effects.

Furthermore, other GPR30 agonists can be found by known methods, which makes it possible to find candidate substances for hair growth. For example, the GPR30 gene can be introduced into various cells such as HEK293 and MCF-7 to produce cells that stably or transiently express GPR30, or commercially available cells that forcibly express GPR30 can be used, and new GPR30 agonists can be screened by observing the activation of GPR30 signals when various substances are contacted with these cells. Substances found by this screening can be used as candidate substances for hair growth. Activation of the GPR30 signal can be detected using known methods (such as increases and decreases in cAMP and calcium as second messengers, and phosphorylation of downstream Erk).

The dosage of G-1 in the present invention is not particularly limited as long as it is within the range that activates GPR30 to some extent, but is preferably 0.0001 to 10% by mass, more preferably 0.001 to 5% by mass, and even more preferably 0.01 to 0.5% by mass.

The hair growth agent or hair loss inhibitor of the present invention can be used as a medicine, quasi-drug, cosmetic, reagent, etc. The dosage form is not particularly limited, but includes external application and internal administration, and is preferably external application to the skin including the scalp and/or hair. When the present invention is applied externally to the skin, examples of the dosage form include lotions, liquids, creams, ointments, gels, sprays, shampoos, conditioners, soaps, etc., and when the present invention is applied internally, examples of the dosage form include tablets, powders, granules, liquids, capsules, dry syrups, jellies, etc.

In addition, as shown in the examples below, the effect has been confirmed in normal mice, and it may be applicable to various types of alopecia and thinning hair other than hair loss thought to be caused by female hormone abnormalities.

The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not limited to these examples.
(Test Example 1) Hair growth test in wild-type G-1 mice
C57BL/6 mice (female, 7 weeks old) were anesthetized, and the hair on the back of the mice was shaved with a razor after applying shaving foam. Three days later, 100 μL of the base or the test solution in which the test substance G-1 was dissolved in the base to the desired dose was administered (applied) to the shaved area of each animal once a day. Ethanol containing 2% dimethyl sulfoxide was used as the base. Using the base group as a comparison example, the hair growth condition was judged from the start of administration using the scores shown in Table 1, and the evaluation was terminated when all animals reached a score of 5.

(Test Example 2) Hair growth test in G-1 GPR30-deficient mice
GPR30-deficient mice were generated by genetically modifying C57BL/6 mice. The mice (female, 7 weeks old) were anesthetized, and shaved with shaving foam. Three days later, 100 μL of a test solution, in which the test substance G-1 was dissolved in a base to the desired dose, was administered (applied) to the shaved area of each animal once a day. Ethanol containing 2% dimethyl sulfoxide was used as the base. The base group was used as a comparison example, and the hair growth status was judged from the start of administration using the scores shown in Table 1. The evaluation was terminated when all individuals reached a score of 5.

<Test result 1>
The change in hair growth score for each group in Test Example 1 is shown in Figure 1. The number of days elapsed on the horizontal axis is counted from the day administration started to the day 1. The G-1 administration group always showed scores equal to or higher than the vehicle group, and showed significantly higher scores than the vehicle group on the 6th, 7th, 9th, and 11th days (*: P<0.05, Wilcoxon test). In other words, the promotion of hair growth by administration of G-1 was confirmed.

<Test result 2>
The change in hair growth score of each group in Test Example 2 is shown in Figure 2. The number of days elapsed on the horizontal axis is set to the first day of administration. Unlike Test Result 1, the G-1 administration group showed scores higher than the vehicle group only at a few points, and there was no point where a significant difference was detected between the scores of both groups (Wilcoxon test), and hair growth was not promoted. In other words, in the absence of GPR30, the hair growth promotion effect of G-1 disappeared.

These results indicate that the presence of GPR30 is necessary for G-1 to exert its hair growth promoting effect, that G-1 indeed exerts its hair growth promoting effect by activating GPR30, and that substances that activate GPR30 can exert a hair growth promoting effect.

The present invention can be used as a medicine, quasi-drug, cosmetic, reagent, etc., intended as a hair growth agent and hair loss inhibitor.

Claims (1)

The following formula [1]
or a pharma- ceutical product thereof, or a solvate thereof.