CN110882260A - Use of 11 β -hydroxysteroid dehydrogenase type 1 enzyme selective inhibitor in preparation of medicine for treating polycystic ovary syndrome - Google Patents

Use of 11 β -hydroxysteroid dehydrogenase type 1 enzyme selective inhibitor in preparation of medicine for treating polycystic ovary syndrome Download PDF

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CN110882260A
CN110882260A CN201911360995.1A CN201911360995A CN110882260A CN 110882260 A CN110882260 A CN 110882260A CN 201911360995 A CN201911360995 A CN 201911360995A CN 110882260 A CN110882260 A CN 110882260A
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孙贇
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Renji Hospital Shanghai Jiaotong University School of Medicine
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Abstract

The invention provides application of an 11 β -hydroxysteroid dehydrogenation type 1 enzyme (11 β -hydroxysteroid dehydrogenase1,11 β -HSD1) inhibitor in preparation of a medicine for treating polycystic ovary syndrome (PCOS), wherein the molecular formula of the 11 β -HSD1 is C17H21ClN4O3S2The structural formula is shown as follows,
Figure DDA0002330221630000011
the invention discovers that the 11 β -HSD1 selective inhibitor can inhibit the activity and expression of 11 β -HSD1 in the ovary part of a PCOS rat, can improve the phenomenon that the concentration of cortisol in the ovary part of the PCOS rat is increased, and simultaneously, the 11 β -HSD1 selective inhibitor can improve the peripheral insulin resistance of the PCOS rat, improve ovulation dysfunction such as follicle growth and development, hormone synthesis and the likeThis suggests that 11 β -HSD1 selective inhibitors have important implications for the treatment of metabolic abnormalities and reproductive dysfunction of PCOS.

Description

Use of 11 β -hydroxysteroid dehydrogenase type 1 enzyme selective inhibitor in preparation of medicine for treating polycystic ovary syndrome
Technical Field
The invention belongs to the field of biological medicines, and relates to a medicine for treating polycystic ovarian syndrome, in particular to application of a selective inhibitor of 11 β -hydroxysteroid dehydrogenase type 1 enzyme in preparation of a medicine for treating polycystic ovarian syndrome.
Background
Polycystic ovary syndrome (PCOS) is the most common disease of abnormal reproductive and endocrine disorders and metabolic disorders in women, the incidence rate of which in women of child bearing age is 9-18%, and the PCOS is the cause of anovulatory infertility in more than 75% of women. PCOS is mainly characterized by dilute ovulation or anovulation, clinical or biochemical hyperandrogenism and ovarian polycystic change, and mainly clinically shows infertility, obesity, insulin resistance and the like, and influences female fertility and metabolic abnormality.
Glucocorticoid is secreted mainly by adrenal gland, has effects of regulating glycolipid metabolism, anti-inflammatory and immunosuppressive, anti-toxic and anti-shock, etc., and is widely used in clinical treatment, glucocorticoid is not only dependent on glucocorticoid in blood circulation, corticoid binding protein level, and glucocorticoid receptor level in tissue, but has been found to be more dependent on subtype and expression of 11 β -HSD in tissue cells, namely 11 β -HSD1 and 11 β -HSD2, which have tissue-specific expression characteristics and exert different effects, 11 β -hydroxysteroid dehydrogenase type 1 (11 β -hydroxysteroid dehydrogenase1,11 β -HSD1) is a key enzyme of cortisol metabolism, having both oxidase and reductase activity, and mainly exerting activity in vivo, converting the activity of NADPH into cortisol without activity, and having activity only on HSD 3884, HSD 4642, and HSD 42, which have activity in vivo+Can inactivate cortisol and convert cortisol into cortisone.
Cortisol plays various important physiological roles in a human body, 11 β -HSDs are expressed to maintain the balance of cortisol in a target organ in the human body, the liver and fat tissues of a PCOS patient, the ovarian local 11 β -HSD1 and the cortisol level are higher than those of healthy people, the peripheral metabolism important target organ liver and the fat tissue 11 β -HSD1 are expressed to cause peripheral insulin resistance, and previous researches show that the regeneration of the cortisol caused by the expression of the ovarian local 11 β -HSD1 can cause the PCOS ovarian local insulin resistance, so that the growth and development of a PCOS follicle and hormone synthesis disorder can be influenced.
A plurality of clinical studies at home and abroad suggest that the cortisol level of the systemic circulation is not influenced, but the diabetes, the cardiac hypertrophy, the hypertension and the non-alcoholic fatty liver disease can be improved by improving the cortisol level of a local target organHowever, whether the 11 β -HSD1 selective inhibitor can treat the PCOS and can improve ovulation failure and metabolic abnormality of the PCOS is not researched at present, BVT2733 is a 11 β -HSD1 selective inhibitor, and the molecular formula of the inhibitor is C17H21ClN4O3S2The structural formula:
Figure BDA0002330221610000021
disclosure of Invention
The invention aims to provide application of a selective inhibitor of 11 β -hydroxysteroid dehydrogenase type 1 enzyme in preparation of a medicine for treating polycystic ovarian syndrome, and the application aims to solve the technical problem that the medicine for treating polycystic ovarian syndrome in the prior art is poor in effect.
The invention provides application of a selective inhibitor of 11 β -hydroxysteroid dehydrogenation type 1 enzyme in preparing a medicament for treating polycystic ovary syndrome, wherein the molecular formula of the 11 β -hydroxysteroid dehydrogenation type 1 enzyme is C17H21ClN4O3S2The structural formula is shown as follows,
Figure BDA0002330221610000022
the invention discovers that a 11 β -hydroxysteroid dehydrogenation type 1 enzyme selective inhibitor BVT2733 can inhibit the activity and expression of 11 β -HSD1, can improve the phenomenon that the concentration of local cortisol in a target organ of PCOS is increased, can improve the peripheral insulin resistance of the PCOS, ovulation disorder, ovarian follicle growth and development and other ovarian dysfunction, has important significance for treating the metabolic abnormality and reproductive disorder of the PCOS, and has important clinical application prospect in the aspect of treating the PCOS.
The application discloses a new application of a 11 β -HSD1 selective inhibitor, namely application of a 11 β -HSD1 selective inhibitor BVT2733 in a medicament for treating polycystic ovary syndrome.
Compared with the prior art, the invention has positive and obvious technical effects, and experimental results show that the 11 β -HSD1 selective inhibitor BVT2733 has comprehensive treatment effect on polycystic ovarian syndrome, the 11 β -HSD1 selective inhibitor BVT2733 can improve polycystic ovarian syndrome rat ovarian polycystic lesion, correct estrus cycle disorder and ovulation disorder shown by polycystic ovarian syndrome, and effectively reduce blood sugar and obesity in the aspect of endocrine metabolism.
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FIG. 1 shows the effect of the 11 β -HSD1 selective inhibitor BVT2733 on PCOS rat ovarian cortisol concentration and 11 β -HSD1 protein expression levels.
FIG. 2 shows the effect of 11 β -HSD1 selective inhibitor BVT2733 on glucose tolerance and insulin tolerance in PCOS rats.
FIG. 3 shows the effect of 11 β -HSD1 selective inhibitor BVT2733 on the size of PCOS rat perigonal adipocytes
FIG. 4 shows the effect of the 11 β -HSD1 selective inhibitor BVT2733 on the estrous cycle in PCOS rats.
FIG. 5 shows the effect of the 11 β -HSD1 selective inhibitor BVT2733 on the PCOS rat ovary.
FIG. 6 shows the effect of the 11 β -HSD1 selective inhibitor BVT2733 on PCOS murine sex hormone.
FIG. 7 shows the effect of the 11 β -HSD1 selective inhibitor BVT2733 on ovulation and ovum quality in PCOS rats.
FIG. 8 shows the effect of the 11 β -HSD1 selective inhibitor BVT2733 on PCOS rat ovarian fibrosis associated protein.
FIG. 9 shows the effect of 11 β -HSD1 selective inhibitor BVT2733 on ovarian fibrosis in PCOS rats
Detailed Description
The drug adopted in the following experiments is BVT2733, is a novel 11 β -HSD1 selective inhibitor, and has the molecular formula of C17H21ClN4O3S2The structural formula is as follows:
Figure BDA0002330221610000031
example 1
Model creation 3 weeks old female SD rats were divided into three groups, control group, PCOS model creation group and PCOS + BVT model creation group, PCOS model creation group was injected subcutaneously with DHEA (6mg/100g body weight) for 21 days, PCOS + BVT model creation group was injected subcutaneously with DHEA (6mg/100g body weight) and perfused with 11 β -HSD1 selective inhibitor BVT2733(10mg/100g body weight) for 21 days, vaginal smear observation estrus cycle was performed every day from 8 days before the end of model creation to determine whether model creation was successful or not, and then sacrificed.
Compared with a control group, the ovarian cortisol concentration and the 11 β -HSD1 protein expression level of rats in the PCOS group are remarkably increased (p is less than 0.05), the ovarian cortisol concentration and the 11 β -HSD1 protein expression level of the rats in the PCOS + BVT model group are remarkably reduced (p is less than 0.05) compared with the rats in the PCOS group, and the results are shown in figure 1, which shows that 11 β -HSD1 selective inhibitor improves the abnormal expression of 11 β -HSD1 locally in ovaries of the rats in the PCOS.
Experimental results 2:
1) compared with the control group, the PCOS group rats have disordered estrus cycles, and the PCOS + BVT model group restores regularity of estrus cycles. The results are shown in FIG. 4.
2) Compared with the control group, the PCOS group rats have increased ovarian antrum follicle number and reduced corpus luteum number. Compared with PCOS rats, PCOS + BVT rats with the model building have the advantages that the ovarian antrum follicles are reduced, and the corpus luteum is increased. The results are shown in FIG. 5.
3) Compared with the control group, the PCOS group rats have sex hormone disorder, and the ratio of luteinizing hormone, luteinizing hormone and follicle-stimulating hormone and the testosterone level are obviously increased (p is less than 0.05). The ratio of luteinizing hormone to follicle stimulating hormone and testosterone level of PCOS + BVT model-building rats are obviously reduced compared with the PCOS rats (p is less than 0.05). The results are shown in FIG. 6.
The results of the above experiments show that a 11 β -HSD1 selective inhibitor improves PCOS rat ovarian function.
Example 2
Glucose tolerance test: after the model is successfully made, fasting is carried out for 16 hours (17: 00-9: 00), and glucose (2g/1000g of body weight) is injected into the abdominal cavity. The blood glucose levels of the rats were measured at 0, 15, 30, 60, 90 and 120 minutes after the glucose injection, respectively.
Insulin tolerance test: after the model is successfully made, the patient is fasted for 4 hours (9: 00-13: 00), and the patient is injected with lilies and secretin (1U/1000g of body weight). The blood glucose levels of the rats were measured at 0, 15, 30, 45 and 60 minutes after insulin injection, respectively.
The experimental results are as follows:
1) compared with the control group, the rats with PCOS group have abnormal glucose tolerance and insulin tolerance and have peripheral insulin resistance, while the rats with PCOS + BVT model group have obviously improved glucose tolerance and insulin tolerance (p is less than 0.001) compared with the rats with PCOS group, and the results are shown in figure 2, and show that 11 β -HSD1 selective inhibitor improves the insulin resistance of the rats with PCOS.
2) Compared with the control group, the rat perigonadal fat cells of the PCOS group are obviously increased, and the rat perigonadal fat cells of the PCOS + BVT modeling group are obviously reduced compared with the rat of the PCOS group. The results are shown in FIG. 3.
Example 3
1. Detection of serum steroid hormones: blood was taken from the abdominal aorta of the rat, centrifuged at 3500rpm, supernatant serum was taken for 10 minutes and stored at-80 ℃. Rat Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) were detected using an ELISA kit (tokyo makino) and Testosterone (Testosterone, T) using an ELISA kit (R & D).
Western Blot protein expression detection tissue was lysed using protein lysate (RIPA extracted total cell protein) on ice, protein concentration was determined using BCA protein quantification kit, 30. mu.g samples were subjected to SDS-PAGE, proteins were transferred to PVDF membrane and then blocked with 5% skim milk-TBST for 2 hours at room temperature, primary antibody was applied overnight in a shaker at 4 ℃ and secondary antibody was incubated for 1 hour at room temperature, ECL luminophore excited fluorescence was applied in G-BOX chemiluminescent exposure was performed using anti-HSD11B1(Abcam), anti-LOX (Abcam), anti-p-ERK (CST), anti-total-ERK (CST), anti-COL4(Novus), anti-p-Akt (CST), anti-Akt (CST), anti-CEBP/β (Santa cruz), and (anti-GAINTECH).
3. The statistical method comprises the following steps: adopting single-factor variance analysis to test whether the mean difference of each group has statistical significance; the checking level is p < 0.05. And (4) performing data statistics and analysis by using SPSS 19.0 statistical software.
4. Ovulation induction experiment: after successful modeling, the rats were injected intraperitoneally with Pregnant Mare Serum (PMSG) 300IU/kg body weight. After the injection of PMSG48 hours, the rats were injected with hCG300IU/kg body weight intraperitoneally. The ova were collected in the oviduct after 16 hours from the injection of hCG.
Experimental result 1:
1) compared with the control group, the PCOS group rats have disordered estrus cycles, and the PCOS + BVT model group restores regularity of estrus cycles. The results are shown in FIG. 4.
2) Compared with the control group, the PCOS group rats have increased ovarian antrum follicle number and reduced corpus luteum number. Compared with PCOS rats, PCOS + BVT rats with the model building have the advantages that the ovarian antrum follicles are reduced, and the corpus luteum is increased. The results are shown in FIG. 5.
3) Compared with the control group, the PCOS group rats have sex hormone disorder, and the ratio of luteinizing hormone, luteinizing hormone and follicle-stimulating hormone and the testosterone level are obviously increased (p is less than 0.05). The ratio of luteinizing hormone to follicle stimulating hormone and testosterone level of PCOS + BVT model-building rats are obviously reduced compared with the PCOS rats (p is less than 0.05). The results are shown in FIG. 6.
The results of the above experiments show that a 11 β -HSD1 selective inhibitor improves PCOS rat ovarian function and hormone synthesis.
Experimental results 2:
1) compared with the control group, the ovulation quantity of the rats in the PCOS group is obviously reduced, the MII egg rate is reduced (p is less than 0.05), and the ovulation quantity (p is less than 0.0001) and the MII egg rate (p is less than 0.05) of the rats in the PCOS + BVT molding group are obviously increased compared with the rats in the PCOS group. The results are shown in FIG. 7.
2) Compared with a control group, the expression levels of the proteins LOX and type IV collagen related to ovarian fibrosis of rats in the PCOS group are obviously increased (p is less than 0.05), and the Masson staining of collagen fibers shows that the ovarian fibrosis degree of the rats in the PCOS group is increased compared with that of the rats in the control group. The expression levels of the ovary fibrosis related protein LOX and the type IV collagen of the PCOS + BVT model-making rats are obviously reduced compared with the PCOS group rats (p is less than 0.05). The results are shown in FIGS. 8-9.
The results of the above experiments show that a 11 β -HSD1 selective inhibitor ameliorates the ovulation failure in PCOS rats.
In conclusion, the 11 β -HSD1 selective inhibitor BVT2733 can effectively inhibit the expression of 11 β -HSD1 protein and the level of cortisol which are increased in PCOS ovaries, and meanwhile, the 11 β -HSD1 selective inhibitor can improve the peripheral metabolic abnormality, ovarian dysfunction, ovulation abnormality and the like of the PCOS, and has an important clinical application prospect in the aspect of treating the PCOS.

Claims (1)

1.11 use of 1.11 β -hydroxysteroid dehydrogenase type 1 enzyme selective inhibitor in preparation of medicine for treating polycystic ovary syndrome, wherein the molecular formula of 11 β -hydroxysteroid dehydrogenase type 1 enzyme is C17H21ClN4O3S2Structural formula is
Figure FDA0002330221600000011
CN201911360995.1A 2019-12-23 2019-12-23 Use of 11 β -hydroxysteroid dehydrogenase type 1 enzyme selective inhibitor in preparation of medicine for treating polycystic ovary syndrome Pending CN110882260A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111743898A (en) * 2020-06-11 2020-10-09 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 Application of 11 beta-HSD 1inhibitor in protecting neural stem cells in stress environment
CN115372482A (en) * 2021-05-17 2022-11-22 上海交通大学医学院附属仁济医院 Application of intestinal flora spectrum and metabolic markers in preparation of polycystic ovarian syndrome diagnostic kit

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CN101111480A (en) * 2004-12-01 2008-01-23 万有制药株式会社 Substituted pyridone derivative

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CN101111480A (en) * 2004-12-01 2008-01-23 万有制药株式会社 Substituted pyridone derivative

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XINYU LI等: "Addressing the role of 11β-hydroxysteroid dehydrogenase type 1 in the development of polycystic ovary syndrome and the putative therapeutic effects of its selective inhibition in a preclinical model", 《METABOLISM CLINICAL AND EXPERIMENTAL》 *
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111743898A (en) * 2020-06-11 2020-10-09 温州医科大学附属第二医院、温州医科大学附属育英儿童医院 Application of 11 beta-HSD 1inhibitor in protecting neural stem cells in stress environment
CN115372482A (en) * 2021-05-17 2022-11-22 上海交通大学医学院附属仁济医院 Application of intestinal flora spectrum and metabolic markers in preparation of polycystic ovarian syndrome diagnostic kit

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Application publication date: 20200317