阅读说明：本技术 11β-羟基类固醇脱氢1型酶选择性抑制剂在制备治疗***的药物中的用途 (Use of 11 β -hydroxysteroid dehydrogenase type 1 enzyme selective inhibitor in preparation of medicine for treating polycystic ovary syndrome ) 是由 孙贇 于 2019-12-23 设计创作，主要内容包括：本发明提供了11β-羟基类固醇脱氢1型酶(11β-hydroxysteroid dehydrogenase 1,11β-HSD1)抑制剂在制备治疗多囊卵巢综合征(polycystic ovary syndrome,PCOS)的药物中的用途,所述的11β-HSD1的分子式为：C<Sub>17</Sub>H<Sub>21</Sub>ClN<Sub>4</Sub>O<Sub>3</Sub>S<Sub>2</Sub>,结构式如下所示,<Image he="282" wi="639" file="DDA0002330221630000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>本发明发现11β-HSD1选择性抑制剂可以抑制PCOS大鼠卵巢局部11β-HSD1活性及表达,能改善PCOS大鼠卵巢局部皮质醇浓度升高的现象,同时11β-HSD1选择性抑制剂不仅能改善PCOS大鼠外周胰岛素抵抗,而且可以改善卵泡生长发育及激素合成等排卵功能障碍。这提示11β-HSD1选择性抑制剂治疗PCOS的代谢异常与生殖功能障碍有着重要意义。(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 C 17 H 21 ClN 4 O 3 S 2 The structural formula is shown as follows, 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.)

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

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:

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,

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.

Drawings

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: