JP7121999B2 - Male hypogonadism therapeutic agent - Google Patents
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- JP7121999B2 JP7121999B2 JP2019175811A JP2019175811A JP7121999B2 JP 7121999 B2 JP7121999 B2 JP 7121999B2 JP 2019175811 A JP2019175811 A JP 2019175811A JP 2019175811 A JP2019175811 A JP 2019175811A JP 7121999 B2 JP7121999 B2 JP 7121999B2
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本発明は、男性性腺機能低下症治療剤に関するものである。 TECHNICAL FIELD The present invention relates to a therapeutic agent for male hypogonadism.
従来より、大腸癌や男性性腺機能低下症は、加齢に伴って発症するリスクが高くなることが知られている。 Conventionally, it has been known that the risk of developing colorectal cancer and male hypogonadism increases with aging.
近年においては、特許文献１や特許文献２などに見られるように、大腸癌治療剤や男性性腺機能低下症治療剤に関する研究が行われている。 In recent years, as seen in Patent Literature 1 and Patent Literature 2, research has been conducted on a therapeutic agent for colorectal cancer and a therapeutic agent for male hypogonadism.
本発明では、大腸癌や男性性腺機能低下症の治療（抑制）に有効に寄与する成分を見出すことを目的とする。 An object of the present invention is to discover a component that effectively contributes to the treatment (suppression) of colon cancer and male hypogonadism.
請求項１に係る本発明では、ＣＨＲ－６４９４を有効成分として含有する男性性腺機能低下症治療剤を提供するものである。 The present invention according to claim 1 provides a therapeutic agent for male hypogonadism containing CHR-6494 as an active ingredient.
本発明では、ＣＨＲ－６４９４によって、男性性腺機能低下症を治療（抑制）することができる。 In the present invention , CHR-6494 can treat (suppress) male hypogonadism.
本発明では、ＣＨＲ－６４９４が大腸癌や男性性腺機能低下症の治療（抑制）に有効に寄与するか否かについて、家族性大腸腫瘍疾患モデルであるApcMin/＋マウスを用いて調べた。 In the present invention, whether or not CHR-6494 effectively contributes to the treatment (suppression) of colorectal cancer and male hypogonadism was investigated using ApcMin/+ mice, a familial colorectal tumor disease model.
ここで、ＣＨＲ－６４９４（化学式［Ｃ１６Ｈ１６Ｎ６］、CAS NO.1333377-65-3）は、ＨＡＳＰＩＮ阻害剤として知られる化学物質である。また、ApcMin/＋マウスは、Apc遺伝子のコドン850にナンセンス突然変異を有する家族性大腸癌モデルマウスである。Apc遺伝子は、大腸癌発症の初期段階に関与している家族性大腸ポリポーシスの原因遺伝子である。JacksonLaboratories（米国メイン州Bar Harbor）によって開発されたApcMin/＋マウス（C57BL/6J)を用いた。 Here, CHR-6494 (chemical formula [C 16 H 16 N 6 ], CAS NO.1333377-65-3) is a chemical substance known as a HASPIN inhibitor. ApcMin/+ mouse is a familial colorectal cancer model mouse having a nonsense mutation at codon 850 of the Apc gene. The Apc gene is a causative gene for familial polyposis of the colon, which is involved in the early stages of colon cancer development. ApcMin/+ mice (C57BL/6J) developed by Jackson Laboratories (Bar Harbor, Maine, USA) were used.
１２匹の雄のApcMin/＋マウスについて、６匹を処置マウスとし、６匹を対照マウスとした。 Of the 12 male ApcMin/+ mice, 6 were treated mice and 6 were control mice.
処置マウスは、１０％ジメチルスルホキシド及び２０％２－ヒドロキシプロピル－ｂ－シクロデキストリンの溶液（Sigma-Aldrich Japan,東京）で希釈したＣＨＲ－６４９４（Cayman Chemical,米国ミシガン州Ann Arbor）を５０mg／kgで約２００μＬ腹腔内に注射処置した（これを、「本処置」という。）。 Treated mice received 50 mg/kg CHR-6494 (Cayman Chemical, Ann Arbor, MI, USA) diluted in a solution of 10% dimethylsulfoxide and 20% 2-hydroxypropyl-b-cyclodextrin (Sigma-Aldrich Japan, Tokyo). Approximately 200 µL of the solution was injected into the peritoneal cavity (this is referred to as "this treatment").
対照マウスは、１０％ジメチルスルホキシド及び２０％２－ヒドロキシプロピル－ｂ－シクロデキストリンの溶液を２００μＬ腹腔内に注射処置した（これを、「対照処置」という。）。 Control mice were treated with a 200 μL intraperitoneal injection of a solution of 10% dimethylsulfoxide and 20% 2-hydroxypropyl-b-cyclodextrin (referred to as “control treatment”).
そして、処置マウスには、５週齢の雄のApcMin/＋マウスに上記本処置を５日間施した後に未処置で５日間飼育し、さらに、５日間の本処置と５日間の未処置を繰り返し行い、あわせて５０日間の処置を行った。 As for the treated mice, 5-week-old male ApcMin/+ mice were subjected to the above treatment for 5 days and then kept untreated for 5 days. for a total of 50 days of treatment.
一方、対照マウスには、５週齢の雄のApcMin/＋マウスに上記対照処置を５日間施した後に未処置で５日間飼育し、さらに、５日間の対照処置と５日間の未処置を繰り返し行い、あわせて５０日間の処置を行った。 On the other hand, as control mice, 5-week-old male ApcMin/+ mice were subjected to the above control treatment for 5 days and then kept untreated for 5 days. for a total of 50 days of treatment.
上記の５０日間にわたる処置を行い、腸ポリープの数や体重を調べるとともに、精巣及び副睾丸の組織を観察し、血清テストステロン値を測定した。 After the above 50-day treatment, the number of intestinal polyps and body weight were examined, the tissue of the testis and epididymis was observed, and the serum testosterone level was measured.
腸ポリープの数は、摘出した小腸の切片を縦方向に切開し、リン酸緩衝食塩水で洗浄し、濾紙上に平らに置き、１０％中性緩衝ホルマリン中で２４時間固定した後に、１％メチレンブルーで染色し、肉眼及び光学顕微鏡によって調べた。 The number of intestinal polyps was determined by longitudinally dissecting excised small bowel segments, rinsing them with phosphate-buffered saline, laying them flat on filter paper, and fixing them in 10% neutral buffered formalin for 24 hours. Stained with methylene blue and examined macroscopically and by light microscopy.
精巣及び副睾丸の組織の観察は、ブアン液で固定した精巣を7μm厚の切片に切断し、シランコートスライドにマウントした後に、スライドを染色して顕微鏡で観察した。 The tissue of the testis and epididymis was observed by cutting the testis fixed with Bouin's solution into 7 μm-thick sections, mounting them on silane-coated slides, staining the slides, and observing them under a microscope.
血清テストステロン値は、液体クロマトグラフィー・タンデム質量分析法によって測定した。 Serum testosterone levels were measured by liquid chromatography-tandem mass spectrometry.
なお、データは、平均値±標準偏差で表し、平均は、スチューデントのｔ検体を用いて比較し、有意差は、P<0.05のレベルで決定した。 The data are expressed as the mean ± standard deviation, the mean was compared using the student's t sample, and the significance of the difference was determined at the level of P < 0.05.
対照マウスと処置マウスの腸ポリープの数を図１に示す。 The numbers of intestinal polyps in control and treated mice are shown in FIG.
対照マウスでは、58.5±17.5であったのに対して、処置マウスでは、24.6±13.8であった。 Control mice had 58.5±17.5, whereas treated mice had 24.6±13.8.
これにより、処置マウスでは、対照マウスよりも有意に少ない数のポリープであることがわかる。 This reveals significantly lower numbers of polyps in treated mice than in control mice.
野生型マウスと処置マウスと対照マウスの体重と精巣重量及び精巣上体重量を図２に示す。 The body weights, testicular weights and epididymal weights of wild-type, treated and control mice are shown in FIG.
対照マウスは、悪液質を発症しており、体重が18.8±1.7ｇであったのに対して、処置マウスは、23.6±4.2ｇであった。 Control mice developed cachexia and weighed 18.8±1.7 g, whereas treated mice weighed 23.6±4.2 g.
これにより、処置マウスでは、対照マウスよりも有意に体重が回復したことがわかる。 This shows that the treated mice regained significantly more weight than the control mice.
処置マウスと対照マウスの精巣及び副睾丸の組織の写真を図３に示す。 Photographs of testicular and epididymal tissue from treated and control mice are shown in FIG.
対照マウスの精巣及び副睾丸の組織の写真（図３Ａ、Ｂ）から対照マウスが性腺機能低下症を発症していることがわかり、精巣重量が0.04±0.03ｇで精巣上体重量が0.006±0.0014ｇであった。 Photographs of testicular and epididymal tissues of control mice (FIGS. 3A, B) showed that control mice developed hypogonadism, with testicular weight of 0.04±0.03 g and epididymal weight of 0.006±0.0014. was g.
これに対して、処置マウスでは、精巣及び副睾丸の組織の写真（図３Ｃ、Ｄ）や精巣重量が0.08±0.03ｇで精巣上体重量が0.0097±0.0012ｇであることから、対照マウスよりも有意に性腺機能低下症から回復したことがわかる。 In contrast, in treated mice, photographs of testicular and epididymal tissue (Fig. 3C, D) and testicular weight of 0.08 ± 0.03 g and epididymal weight of 0.0097 ± 0.0012 g indicate that It can be seen that significantly recovered from hypogonadism.
対照マウスと処置マウスの血中テストステロン値を図４に示す。 Blood testosterone levels in control and treated mice are shown in FIG.
対照マウスは、17.0±6.6pg/mLであったのに対して、処置マウスは、144.2±120.0pg/mLであった。 Control mice had 17.0±6.6 pg/mL, while treated mice had 144.2±120.0 pg/mL.
これにより、処置マウスでは、対照マウスよりも有意に回復したことがわかる。 This shows that the treated mice recovered significantly more than the control mice.
以上に説明したように、対照マウスすなわちApcMin/＋マウスは、加齢に伴って腸ポリープ数が増加し、悪液質を発症し、また、性腺機能低下症を発症したのに対して、処置マウスすなわちＣＨＲ－６４９４を投与したマウスでは、加齢に伴う腸ポリープ数の増加や悪液質及び性腺機能低下症の発症が有意に抑制されていることがわかった。 As explained above, control or ApcMin/+ mice had an increased number of intestinal polyps, developed cachexia, and developed hypogonadism with age, whereas treated It was found that the age-related increase in the number of intestinal polyps and the development of cachexia and hypogonadism were significantly suppressed in mice, ie, mice administered with CHR-6494.
これらのことから、ＣＨＲ－６４９４は、大腸癌や男性性腺機能低下症の発症を治療（抑制）する成分として有効に寄与するといえ、大腸癌治療剤（大腸癌抑制剤）や男性性腺機能低下症治療剤（男性性腺機能低下症抑制剤）として有用であるといえる。 From these facts, it can be said that CHR-6494 effectively contributes as a component to treat (suppress) the onset of colon cancer and male hypogonadism. It can be said that it is useful as a therapeutic agent (male hypogonadism inhibitor).
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002087964A (en) | 2000-08-31 | 2002-03-27 | Unimed Pharmaceuticals Inc | Pharmaceutical composition and method for treating hypogonadism |
| JP2013510824A (en) | 2009-11-12 | 2013-03-28 | セルビタ エス．エー． | Compounds for modulating or controlling serine / threonine kinases, methods for their preparation, pharmaceutical compositions, use of compounds, methods and serine / threonine kinase modulators |
| JP2014528932A (en) | 2011-09-08 | 2014-10-30 | ノバルティス アーゲー | Use of an aromatase inhibitor for the treatment of hypogonadism and related diseases |
| JP2017507975A (en) | 2014-03-10 | 2017-03-23 | アンドルシェルシュ・インコーポレイテッド | Treatment of male androgen deficiency symptoms or diseases by combined use of sex steroid precursor and SERM |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002087964A (en) | 2000-08-31 | 2002-03-27 | Unimed Pharmaceuticals Inc | Pharmaceutical composition and method for treating hypogonadism |
| JP2013510824A (en) | 2009-11-12 | 2013-03-28 | セルビタ エス．エー． | Compounds for modulating or controlling serine / threonine kinases, methods for their preparation, pharmaceutical compositions, use of compounds, methods and serine / threonine kinase modulators |
| JP2014528932A (en) | 2011-09-08 | 2014-10-30 | ノバルティス アーゲー | Use of an aromatase inhibitor for the treatment of hypogonadism and related diseases |
| JP2017507975A (en) | 2014-03-10 | 2017-03-23 | アンドルシェルシュ・インコーポレイテッド | Treatment of male androgen deficiency symptoms or diseases by combined use of sex steroid precursor and SERM |
Non-Patent Citations (2)
| Title |
|---|
| Oncogene，2012年，Vol.31，pp.1408-1418 |
| 新潟がんセンター病院医誌，2018年 |
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