CN113143928A - 一种osi-906的应用 - Google Patents
一种osi-906的应用 Download PDFInfo
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- CN113143928A CN113143928A CN202110363642.8A CN202110363642A CN113143928A CN 113143928 A CN113143928 A CN 113143928A CN 202110363642 A CN202110363642 A CN 202110363642A CN 113143928 A CN113143928 A CN 113143928A
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Abstract
本发明提供了一种OSI‑906的应用，涉及生物医药领域。OSI‑906是一种小分子化合物，其在人体内可以抑制酪氨酸激酶受体IGF‑1R的信号传导、增值和细胞因子分泌，可以用于相关疾病的治疗，例如甲状腺相关眼病、炎症性皮肤病、全身黏液性水肿、胫前黏液性水肿、多囊卵巢综合症、高雄激素血症、子宫内膜异位症相关疼痛、系统性硬化症等。
Description
技术领域
本发明属于生物医药领域，涉及一种OSI-906的应用。
背景技术
IGF-1R属于酪氨酸蛋白激酶受体家族，是一种细胞表面的跨膜蛋白，可被IGF-1及IGF-2(均为胰岛素增长因子)激活，其过度表达可能与多发性硬化、克罗恩病、肺纤维化等恶性肿瘤及自身免疫性疾病发病相关。胰岛素生长因子1受体(IGF-1R)抑制剂可作为抗癌细胞生长的选择性抑制剂。近年来，以IGF-1R为靶点的小分子激酶抑制剂有了迅速的发展。
OSI-906本领域研究人员发现的新颖的小分子IGF-1R抑制剂，其可以通过阻断MAPK和PI3K-Akt通路有效的选择性抑制IGF-1R的自身磷酸化。在体内实验中，OSI-906对多种肿瘤细胞的增值扩散有明显的抑制作用，表现出非常强的抗肿瘤功效。如专利申请US2010033825公开了一种OSI-906治疗肾上腺皮质癌的方法。专利申请US13203254公开了一种治疗患者肿瘤或肿瘤转移的方法，其中包括向患者施用有效量的小分子IGF-1R激酶抑制剂OSI-906。
目前对于OSI-906应用的研究多针对某些肿瘤和癌症的治疗，尚无使用IGF-1R小分子抑制剂在治疗甲状腺眼病中的报道。
甲状腺相关性眼病(thyroid associated ophthalmopathy，TAO)又名内分泌突眼、浸润性突眼、甲状腺眼病，约占眼眶疾病的20％。甲状腺相关性眼病可引起眼球突出、眼睑挛缩、眼外肌功能障碍、球结膜充血、眶周水肿等，严重时会导致暴露性角膜炎、复视和压迫性视神经病变，后者可导致失明，严重影响患者的生活质量。甲状腺相关性眼病是由甲状腺上皮细胞、眼眶前脂肪细胞及成纤维细胞一起表达的共同抗原引发的以细胞免疫为主的位点特异性自身免疫疾病。炎症反应、眼眶成纤维细胞增多和眼眶脂肪细胞的增多导致眼球突出，引发甲状腺相关性眼病的症状。胰岛素样生长因子1受体(insulin-like growthfactor 1receptor，IGF-1R)和促甲状腺激素受体(thyroid-stimulating hormonereceptor，TSHR)在甲状腺相关性眼病患者眼眶成纤维细胞中的水平异常偏高，且二者间存在着复杂的信号通路网络联系，与疾病的发生密切相关。大部分的甲状腺眼病患者体内可以检测到抗IGF-1R的抗体，而正常人体内少有发现。IGF-1R或甲状腺眼病相关的IgG可激活甲状腺相关性眼病患者来源的IGF-1R阳性的眼眶成纤维细胞，从而激活Akt/FRAP/mTOR/P70s6k通道诱导眼眶成纤维细胞上白细胞介素-16和调节活化正常T细胞表达和分泌的因子(regulated upon activation normal T cell expressed and secreted factor，RANTES)的表达，促进T细胞趋化因子的合成，引起T淋巴细胞的炎性浸润和透明质酸的产生，这些都表明IGF-1R可能作为第二抗原参与了甲状腺眼病的发展。IGF-1R与TSHR的下游信号有大量重叠，阻断IGF-1R的信号传导，及减弱TSHR通路的下游信号，可以减轻促甲状腺激素引起的炎症反应，提示IGF-1R参与了TSHR信号传导，并且IGF-1R与TSHR可能形成了一个复杂的功能复合体，在甲状腺眼病相关的异常信号传导方面起着协同作用。
同样的，炎症性皮肤病、全身黏液性水肿、胫前黏液性水肿、多囊卵巢综合症、高雄激素血症、子宫内膜异位症相关疼痛、系统性硬化症等疾病，研究也检测到患者体内有抗IGF-1R的抗体的出现，其发病与IGF-1R在体内的信号传播有很大的相关性。可以预见的是，利用OSI-906阻断IGF-1R的信号传导的效果，能够有效预防和治疗相关疾病。
发明内容
本发明针对现有技术存在的问题，提供了一种OSI-906的应用。小分子化合物抑制剂OSI-906能够应用于相关疾病如甲状腺相关眼病、炎症性皮肤病、多囊卵巢综合症等的治疗。
为实现上述目的，本发明采用的技术方案如下：
OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗甲状腺相关眼病的药物中的应用，其中所述的甲状腺相关眼病为眼球突出、眼睑退缩、上睑迟落、眼外肌肥大、结膜充血、眶周组织水肿、眼睑闭合不全、畏光、流泪、异物感、视力下降或复视中的一种或几种；其中OSI-906的结构如下所示：
OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗炎症性皮肤病的药物中的应用，其中所述的炎症性皮肤病为痤疮、银屑病、特应性皮炎、脂溢性皮炎、湿疹、过敏性紫癜、病理性瘢痕或系统性红斑狼疮中的一种或几种。
OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗全身黏液性水肿、胫前黏液性水肿的药物中的应用，其中所述全身黏液性水肿为真性黏液性水肿；所述胫前黏液性水肿为甲状腺毒性黏蛋白沉积症。
OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗多囊卵巢综合症的药物中的应用，其中所述多囊卵巢综合症为排卵障碍、女性不孕、早期流产或月经不调中的一种或几种。
OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗多高雄激素血症的药物中的应用，其中所述高雄激素血症为脂溢性皮炎、痤疮、粉刺、脱发或肥胖中的一种或几种。
OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗子宫内膜异位症相关疼痛的药物中的应用。
OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗系统性硬化症的药物中的应用。
进一步地，所述药学上可接受的盐选自盐酸盐、硫酸盐、磷酸盐、乙酸盐、L-乳酸盐、马来酸盐、富马酸盐、琥珀酸盐、L-苹果酸盐、己二酸盐、L-酒石酸盐、马尿酸盐、柠檬酸盐、粘酸盐、乙醇酸盐、D-葡萄糖醛酸盐、苯甲酸盐、龙胆酸盐、烟酸盐、乙二磺酸盐、草酸盐、甲磺酸盐、苯磺酸盐、2-羟基乙磺酸盐或氢溴酸盐中的一种或几种。
进一步地，所述OSI-906，或其药学上可接受的盐为无水形式、水合物形式或溶剂合物形式。
进一步地，所述溶剂合物为甲醇溶剂合物或乙酸乙酯溶剂合物。
相对于现有技术，本发明扩充了OSI-906的应用范围和适应症，为甲状腺相关眼病、炎症性皮肤病、全身黏液性水肿、胫前黏液性水肿、多囊卵巢综合症、高雄激素血症、子宫内膜异位症相关疼痛、系统性硬化症等疾病的治疗找到了一种新的有效的药物。
附图说明
图1为正常对照组大鼠眼外肌光镜图；
图2为造模对照组大鼠眼外肌光镜图；
图3为造模给药组大鼠眼外肌光镜图；
图4为化合物Ⅰ组大鼠眼外肌光镜图；
图5为化合物Ⅱ组大鼠眼外肌光镜图；
图6为化合物Ⅲ组大鼠眼外肌光镜图。
具体实施方式
为使本发明的目的、技术方案和优点更加清楚明白，以下结合具体实施例，对本发明进一步详细说明。但下述实施例仅仅为本发明的优选实施例，并非全部。为了清楚，不描述实际实施例的全部特征。基于实施方式中的实施例，本领域技术人员在没有做出创造性劳动的前提下所获得其它实施例，都属于本发明的保护范围。
下述实施例中的实验方法，如无特殊说明，均为常规方法，下述实施例中所用的材料、试剂等，如无特殊说明，均可从商业途径得到。其中：
CellTiterGlo仪器购自于美国Promega，Madison；
牛甲状腺球蛋白购自于Sigma-Aldrich，货号为609310；
OSI-906购于上海瀚香生物科技有限公司，货号为BCP01831；
PBS购于赛默飞世尔科技(中国)有限公司，货号为10010023；
MCF-7购于中国科学院细胞库，货号为TCHu 74。
实施例1 OSI-906对IGF-1R的抑制作用
IGF-1R的过度表达和激活可以促进肿瘤细胞的增殖，通过添加不同浓度的化合物可以检测化合物对于细胞增殖抑制的IC50结果。将OSI-906稀释成不同的终浓度与人乳腺癌细胞MCF-7在96孔板中铺板共同培养3天，血清浓度10％，细胞的生长抑制情况通过CellTiterGlo仪器进行检测。通过对不同浓度OSI-906与细胞数量(以测得的胞外ATP的荧光强度计算)的对应关系进行计算、拟合获得OSI-906的IC50值为177nM。
实施例2 OSI-906在甲亢动物模型中的药效
通过腹腔注射牛甲状腺球蛋白诱导大鼠甲状腺功能亢进及甲状腺相关眼病模型，观察OSI-906对大鼠甲状腺相关眼病的影响，包括以下步骤：
(1)选取成年健康雄性SD大鼠，随机分成3组，每组十只，分别为正常对照组、造模对照组和造模给药组。模型组大鼠每2周按150μg/只的剂量腹腔注射牛甲状腺球蛋白进行造模，持续4周完成造模。具体给药方案按照表1操作：
表1
(2)给药4周后安乐死动物进行取材。将大鼠安乐死后眼外肌取材，进行组织染色，光镜下采图观察。结果如图1-3所示：
正常对照组可见肌纤维均质红染，排列整齐，肌间毛细血管丰富，肌间距正常；
造模对照组可见各类眼外肌病变，主要包括肌纤维严重肿胀、变性、坏死、溶解，肌间距缩窄或增宽，肌间纤维结缔组织和血管增生，提示SD大鼠甲状腺眼病模型成功建立；
造模给药组病变轻微，肌纤维排列基本整齐，可见部分肌纤维轻微肿胀或变性，说明造模给药组药物治疗SD大鼠甲状腺眼病有良好的效果。
实施例3 OSI-906在多囊卵巢综合征动物模型中的药效
在SD雌性大鼠体内通过皮下注射双氢睾酮进行多囊卵巢综合征造模，选取通过监测大鼠体重增加的变化情况、闭锁卵泡数量、阴道涂片中上皮细胞的变化评估OSI-906在模型中的药效，具体包括以下步骤：
(1)选取成年健康出生天数近似、体重体脂近似的雌性SD大鼠，随机分成3组，每组十只，分别为正常对照组、造模对照组和造模给药组，分组后各组大鼠体重均无显著差异。相同条件下饲养，模型组大鼠每2周按250μg/只的剂量皮下注射双氢睾酮进行造模，持续4周完成造模。具体给药方案按照表2操作：
表2
(2)实验结果：
与正常对照组相比较，造模组的大鼠阴道上皮出现持续角化，出现大量闭锁卵泡，说明造模成功；而造模给药组的大鼠阴道上皮出现角化情况较轻微，同时闭锁卵泡的出现数量也较造模组少。因此OSI-906具有改善动物模型多囊卵巢综合征的效果。
实施例4 OSI-906在炎症性皮肤病动物模型中的药效
通过对SD大鼠耳廓注射痤疮丙酸杆菌的方式进行痤疮动物模型造模，在造模当天进行给药，通过测定造模部位的皮肤评分进行OSI-906的治疗效果，包括以下步骤：
(1)选取成年健康的雄性SD大鼠，随机分成3组，每组十只，分别为正常对照组、造模对照组和造模给药组，分组后各组大鼠皮肤状况均无显著差异。相同条件下饲养，模型组大鼠耳廓皮内进行50ul(浓度6×107CFU/ml)痤疮丙酸杆菌菌液注射进行造模，持续4周完成造模。具体给药方案按照表3操作：
表3
(2)实验结果：
正常对照组大鼠的耳廓局部组织未出现增厚、变硬或脓肿，注射部位无红斑和水肿，皮肤表面光滑；造模组大鼠的耳廓局部组织出现增厚、变硬，皮肤粗糙隆起呈丘疹，出现脓肿，有些部位形成硬结样白头粉刺；造模给药组大鼠的耳廓局部组织出现轻微增厚，皮肤表面整体较光滑，未见脓肿或丘疹样病变。因此OSI-906具有改善痤疮外观的效果。
对比例1其他常见IGF-1R抑制剂对IGF-1R的抑制作用
与实施例1的区别在于将OSI-906分别替换成化合物Ⅰ、化合物Ⅱ和化合物Ⅲ。其中，三种化合物的结构式如下所示：
测得IC50结果如表4所示。
表4
| 化合物代码 | IC<sub>50</sub> |
| Ⅰ | 200nM |
| Ⅱ | 90000nM |
| Ⅲ | 218nM |
对比例2其他常见的IGF-1R抑制剂在动物模型中的药效
与实施例2不同的是，将OSI-906换成对比例1所述的三种化合物，其余皆相同。具体操作为：
(1)选取成年健康的雄性SD大鼠，随机分成3组，每组十只，按照给药情况分为化合物Ⅰ组，化合物Ⅱ组和化合物Ⅲ组，分组后各组大鼠眼部均健康无显著差异。3组大鼠每2周按150μg/只的剂量腹腔注射牛甲状腺球蛋白进行造模，持续4周完成造模。具体给药方案按照表5操作：
表5
(2)给药4周后安乐死动物进行取材。将大鼠安乐死后眼外肌取材，进行组织染色，光镜下采图观察。结果如图4-6所示，光镜结果显示，三组均出现了不同程度的眼外肌病变，主要体现在肌纤维轻微肿胀、变性，肌间纤维结缔组织和血管增生。总的来说化合物Ⅲ组显示出优于化合物Ⅰ组和化合物Ⅱ组，但是化合物Ⅲ组仍有较大区域的眼外肌出现了变形，且该结果劣于实施例1中OSI-906组。
最后应当说明的是，以上内容仅用以说明本发明的技术方案，而非对本发明保护范围的限制，本领域的普通技术人员对本发明的技术方案进行的简单修改或者等同替换，均不脱离本发明技术方案的实质和范围。
Claims (10)
1.OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗甲状腺相关眼病的药物中的应用，其中所述的甲状腺相关眼病为眼球突出、眼睑退缩、上睑迟落、眼外肌肥大、结膜充血、眶周组织水肿、眼睑闭合不全、畏光、流泪、异物感、视力下降或复视中的一种或几种；其中OSI-906的结构如下所示：
2.OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗炎症性皮肤病的药物中的应用，其中所述的炎症性皮肤病为痤疮、银屑病、特应性皮炎、脂溢性皮炎、湿疹、过敏性紫癜、病理性瘢痕或系统性红斑狼疮中的一种或几种。
3.OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗全身黏液性水肿、胫前黏液性水肿的药物中的应用，其中所述全身黏液性水肿为真性黏液性水肿；所述胫前黏液性水肿为甲状腺毒性黏蛋白沉积症。
4.OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗多囊卵巢综合症的药物中的应用，其中所述多囊卵巢综合症为排卵障碍、女性不孕、早期流产或月经不调中的一种或几种。
5.OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗多高雄激素血症的药物中的应用，其中所述高雄激素血症为脂溢性皮炎、痤疮、粉刺、脱发或肥胖中的一种或几种。
6.OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗子宫内膜异位症相关疼痛的药物中的应用。
7.OSI-906，或其药学可接受的盐或立体异构体在制备用于治疗系统性硬化症的药物中的应用。
8.根据权利要求1-7任一项所述的应用，其特征在于，所述药学上可接受的盐选自盐酸盐、硫酸盐、磷酸盐、乙酸盐、L-乳酸盐、马来酸盐、富马酸盐、琥珀酸盐、L-苹果酸盐、己二酸盐、L-酒石酸盐、马尿酸盐、柠檬酸盐、粘酸盐、乙醇酸盐、D-葡萄糖醛酸盐、苯甲酸盐、龙胆酸盐、烟酸盐、乙二磺酸盐、草酸盐、甲磺酸盐、苯磺酸盐、2-羟基乙磺酸盐或氢溴酸盐中的一种或几种。
9.根据权利要求8所述的应用，其特征在于：所述OSI-906，或其药学上可接受的盐为无水形式、水合物形式或溶剂合物形式。
10.根据权利要求9所述的应用，其特征在于：所述溶剂合物为甲醇溶剂合物或乙酸乙酯溶剂合物。
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| WO2022206339A1 (zh) * | 2021-04-02 | 2022-10-06 | 苏州普乐康医药科技有限公司 | 一种osi-906的应用 |
| WO2024069236A1 (en) * | 2022-09-30 | 2024-04-04 | Horizon Therapeutics Ireland Dac | Methods for treating inactive or chronic thyroid eye disease |
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| CN103025734A (zh) * | 2010-07-30 | 2013-04-03 | Osi药物有限责任公司 | 制备化合物osi-906的方法 |
| WO2021041773A1 (en) * | 2019-08-28 | 2021-03-04 | Hznp Limited | Methods for the treatment of thyroid eye disease |
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| WO2018077889A1 (en) * | 2016-10-24 | 2018-05-03 | Almirall, S.A. | Compositions comprising linsitinib |
| CN113143928A (zh) * | 2021-04-02 | 2021-07-23 | 苏州普乐康医药科技有限公司 | 一种osi-906的应用 |
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| CN103025734A (zh) * | 2010-07-30 | 2013-04-03 | Osi药物有限责任公司 | 制备化合物osi-906的方法 |
| WO2021041773A1 (en) * | 2019-08-28 | 2021-03-04 | Hznp Limited | Methods for the treatment of thyroid eye disease |
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| WO2022206339A1 (zh) * | 2021-04-02 | 2022-10-06 | 苏州普乐康医药科技有限公司 | 一种osi-906的应用 |
| WO2024069236A1 (en) * | 2022-09-30 | 2024-04-04 | Horizon Therapeutics Ireland Dac | Methods for treating inactive or chronic thyroid eye disease |
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