CN111840285A - Gpr17和/或csfr1受体抑制剂 - Google Patents
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Abstract
本发明涉及一种GPR17和/或CSFR1受体抑制剂。本发明公开了式(I)和式(II)所示的化合物中的至少一种在制备GPR17和/或CSFR1受体抑制剂中的应用。本发明的式(I)和式(II)所示的化合物可作用于CSFR1抑制小胶质细胞活化，并可作用于GPR17促进髓鞘保护，可用于制备预防和/或治疗中枢神经系统损伤和PV神经元数量减少或功能异常的神经退行性疾病。
Description
技术领域
本发明涉及作用于GPR17和/或CSFR1的化合物，尤其涉及一种GPR17和/或CSFR1受体抑制剂。
背景技术
集落刺激因子受体1(CSFR1)是位于骨髓祖细胞、巨噬细胞和其它单核细胞表面的重要生长因子受体，通过与CSFR1结合调控单核细胞的生长和分化。现已证实CSF1R的多种抑制剂可单独或联合其它药物用于单核细胞增殖相关肿瘤的临床实验，并取得了良好的进展。有研究报道CSFR1的抑制剂PLX3397可抑制听力损伤导致皮质中小胶质细胞的活化和相应的耳鸣症状。虽然，目前已有大量研究证实中枢系统损伤、退行性变以及多种疾病与小胶质细胞的异常活化相关，或长期持续性损伤、病变、传入缺失会引发小胶质细胞的活化，但目前应用小胶质细胞抑制剂来治疗脑皮质小胶质细胞过度活化或引发的有关退行性变相关疾病的药物尚未进入临床。
G蛋白偶联受体17(GPR17)结构介于半胱氨酰白三烯受体基团和嘌呤P2Y亚家族受体之间，与它们的氨基酸同源性为28％到48％。GRP17是G蛋白偶联受体，主要通过与Gialpha亚基连接的G蛋白起作用，同时也与Gqalpha亚基相连。基于以上功能，研究发现GPR17可以被半胱氨酰白三烯(LTC4和LTD4)以及嘌呤(即尿苷，二磷酸尿苷)激活，同时，它还可以介导细胞反应中某些相关半胱氨酰白三烯或嘌呤受体二聚化，并且这种二聚化报道与这些配体激活GRP17在不同细胞中表达的能力差异变化。另外，GPR17还可以通过紧急信号和促进动脉粥样硬化的固醇以及具有广泛不同结构的合成化合物激活。这些与它的配体活化以及其它G蛋白偶联受体的相互作用有关。目前，其相关信号通路抑制剂Montelukast作用于半胱氨酰白三烯受体1，被应用于临床LTC4和LTD4引发的过敏性和非过敏性疾病的长期和预防性治疗；而Cangrelor抑制P2Y嘌呤过敏性受体在美国被批准作为抗血小板药物。
GPR17首先被克隆自中枢神经系统组织的少突胶质细胞的前体细胞。在脱髓鞘损伤的中枢神经系统组织中高表达，在损伤发生48小时内，GPR17在损伤中的神经元细胞、浸润的小胶质细胞和巨噬细胞以及活化的少突胶质前体细胞中被诱导表达。有关神经组织疾病研究发现，GPR17在成熟少突胶质细胞前体中高表达，但在成熟少突胶质细胞中不表达，所以必须下调GPR17才能促使前体细胞分化成为具有促进髓鞘产生和形成的少突胶质细胞。同时研究还发现在缺血、实验性脑炎(EAE)和局灶性脱髓鞘的动物模型的中枢神经系统组织中，因缺血、创伤和多发性硬化而遭受脑损伤患者的中枢组织中GPR17表达显著升高。而使用GPR17抑制剂—Montelukast，可减轻年龄相关认知障碍大鼠模型的炎症反应，促进海马神经再生，改善学习和记忆。研究还发现GPR17是中枢神经系统损伤的传感器，通过清除和/或促进由各种损伤(包括衰老)引发的受损神经元的再髓鞘化来参与损伤修复。现GPR17已被提议作为治疗人类多发性硬化和脑外伤的重要候选药物靶点，但相关药物尚未进入临床应用。
临床脑组织病变大多与脑组织缺血、缺氧、外伤、感染、蛋白异常沉积、神经元兴奋性异常、传入缺失有关。近年来研究发现，在损伤急性期或经过长时间神经传入缺失会导致小胶质细胞的活化。随后，小胶质细胞分化成为M1和M2型细胞，继而发挥其炎症反应调节以及神经元营养和修复功能。在剧烈环境变化和损伤急性反应期，这些小胶质细胞会分化成为具有炎症调节作用的M1型细胞，起到清除病原微生物、异物、异常沉积蛋白、阻断外周组织感染等作用。小胶质细胞的活化进一步引发星形细胞和其它中枢神经组织内炎症相关细胞的活化和反应。另一方面过度清除小胶质细胞会影响中枢神经系统的免疫平衡，继而引发“胶质细胞炎症因子风暴”，造成星形细胞的过度增多来弥补小胶质细胞的功能。这些中枢神经系统免疫细胞的异常活化均可导致少突胶质细胞形成髓鞘保护的功能受到严重影响，从而导致多种神经元功能异常、损伤、死亡相关退行性病变。虽然有文献报道在使用CSF1R抑制剂清除大部分小胶质细胞后，神经元细胞的髓鞘保护可增强，但其中的机制尚未阐明，并存在引发“胶质细胞炎症因子风暴”。然而，异常活化的小胶质细胞的残留则有可能引发长期的慢性炎症反应，进一步影响神经元细胞以及少突胶质细胞的髓鞘保护功能。所以，有关抑制剂在临床的应用安全仍需深入探讨。
近年来研究发现听力下降是诱发老年痴呆症的独立危险因素，而且可能是老年痴呆最早期的表现，听力每下降10dB，认知能力可能“早衰”4年，这会加速老年痴呆的出现。随着年龄增长，人的听力开始进行性退化，很多人觉得这是自然而然的衰老。但是，老年人听力下降后，传入大脑的信号减少，久而久之大脑中相应的听觉中枢部分会发生退行性改变。由于听觉信息的抽象性和复杂性，听觉中枢功能退化，会造成整个大脑的分析处理功能退化。研究发现轻度听力损失的人与听力正常的人比，日后患痴呆症的可能性要高出两倍，中度听力损失的人会高出3倍，而对于重度听力损失的人，则高达5倍。听力下降可能是痴呆最早期的表现，而我国对老年人听力下降正确干预率不足1/5。老年人听力下降，主要是听觉神经系统发生了退行性改变，从而破坏大脑中神经细胞间的信号和通信，导致老年人常常不得不花费更多的努力去听，并经常得到更糟糕的结果。听力下降的另一问题体现在一般老年人在嘈杂环境里很难理解别人的话语，该问题可能来源于两种退化，一种是实质性的听力损失，另一种是大脑处理问题能力的损失。而后者的出现则意味着，即使是佩戴助听器(解决听力损失问题)，也不能解决听觉系统从外界环境获取有用信息的问题。这些发现揭示了老年人大脑的神经退行性变化对听力影响的重要作用，所以在分子水平上理解大脑的退行性变机制，将有助于寻找可以靶向预防或治疗听力损失的途径和有效策略。
研究发现随着年龄的增长，Parvalbumin(PV)神经元，一种重要的抑制性神经元的数量减少。而该神经元的数量减少或功能下降与多种神经退行性疾病相关，如阿尔茨海默病等，但其内在机制仍待阐明。目前临床上尚没有有效抑制PV神经元损伤或数量减少的有效药物。研究证实PV神经元细胞的轴突直径与普通锥体细胞相比较细，而少突胶质细胞对较细轴突的识别和保护功能较差。一旦损伤，后续的修复可能无法完成，继而造成神经元细胞的功能异常或死亡。所以，保护少突胶质细胞对于PV神经元的功能维持极为重要。
发明内容
为解决上述技术问题，本发明的目的是提供一种GPR17和/或CSFR1受体抑制剂，本发明的式(I)和式(II)所示的化合物可作用于CSFR1抑制小胶质细胞活化，并可作用于GPR17促进髓鞘保护，可用于制备预防和/或治疗中枢神经系统损伤和PV神经元数量减少或功能异常的神经退行性疾病。
本发明的目的是公开式(I)和式(II)所示的化合物中的至少一种在制备GPR17和/或CSFR1受体抑制剂中的应用：
其中，A1选自NH、S或O；
A2选自C、N、S或O；
R1、R2和R3分别独立地选自氢、卤素、氰基、叠氮基、硝基或C1-C6烷氧基羰基氨基；
其中，A选自氢、卤素、氰基、叠氮基、硝基或酰胺键；
R5和R6分别独立地选自氢、卤素、氰基、叠氮基、硝基或戊唑基。
本发明的式(I)中，“C1-C6烷氧基羰基氨基”的结构通式为R-O-CO-NH-，其中，R代表C1-C6烷基，优选为C3-C6环烷基。
更优选地，式(I)所示的化合物包括以下结构式：
优选地，式(II)所示的化合物包括以下结构式：
优选地，式(I)和式(II)所示的化合物中的至少一种用于制备GPR17和CSFR1受体抑制剂。
进一步地，GPR17和/或CSFR1受体抑制剂用于制备治疗和/或预防神经退行性疾病的药物。
进一步地，神经退行性疾病由抑制性神经元损伤引起，神经退行性疾病包括多发性硬化症、阿尔茨海默氏病、痴呆、听觉过敏、偏头痛、噪音致耳聋引发的继发性耳鸣、神经传入缺失引发的神经痛等疾病。
进一步地，GPR17受体抑制剂用于制备治疗和/或预防GPR17介导的髓鞘形成障碍相关疾病的药物。
进一步地，GPR17介导的髓鞘形成障碍相关疾病包括多发性硬化症、阿尔茨海默氏病、痴呆、听觉过敏、偏头痛、噪音致耳聋引发的继发性耳鸣等疾病。
进一步地，CSFR1受体抑制剂用于制备治疗和/或预防因小胶质细胞异常活化导致的疾病。
进一步地，因小胶质细胞异常活化导致的疾病包括多发性硬化症、听觉过敏、偏头痛、噪音致耳聋引发的继发性耳鸣以及神经传入缺失引发的神经痛等疾病。
借由上述方案，本发明至少具有以下优点：
本发明公开了作用于GPR17和CSFR1的化合物，这些化合物同时具有促进髓鞘形成和清除小胶质细胞的功能，可及时保护损伤中的神经元细胞功能，减少损伤对其髓鞘保护造成的影响，尤其对于炎症和髓鞘减少可能同时存在的病变极为重要。
本发明的化合物用于制备治疗因小胶质细胞异常活化以及GRP17介导的髓鞘形成减少的临床相关疾病的药物；用于制备预防和/或治疗髓鞘形成障碍和与脑组织损伤相关的综合征或神经、精神障碍时，可向有此需要的患者给予治疗有效量的本发明的上述化合物。
上述说明仅是本发明技术方案的概述，为了能够更清楚了解本发明的技术手段，并可依照说明书的内容予以实施，以下以本发明的较佳实施例并配合详细附图说明如后。
附图说明
图1是实施例3中不同实验组小鼠听觉皮层神经元髓鞘荧光测试结果。
具体实施方式
下面结合实施例，对本发明的具体实施方式作进一步详细描述。以下实施例用于说明本发明，但不用来限制本发明的范围。
实施例1 GPR17和CSFR1抑制活性测试实验
为了测试本发明两类化合物对GPR17和CSFR1的抑制活性，以下进行抑制活性测试实验。其中所用到的化合物包括化合物I、化合物II、Montelukast(购买自TCI)和PLX3397(购买自Sigma)，其他用到的试剂均可通过商业途径获得。Montelukast和PLX3397分别作为GPR17和CSFR1受体抑制剂的阳性对照。化合物I、化合物II的结构式依次如下：
实验所用细胞包括分别稳定表达GPR17/Gal6和CSFR1/Gal6的HEK293细胞。
将化合物I、化合物II、Montelukast和PLX3397分别用DMSO溶解，得到4种待测药物溶液，并于4℃下保存。将稳定表达GPR17/Gal6或CSFR1/Gal6的HEK293细胞接种于96孔板，培养过夜。第二天，弃去培养液，加入新配制的显色染料(Fluo-4/AM)40μL/孔，置5％CO2，37℃培养40min。用钙缓冲液分别将4种待测药物溶液稀释并混匀，得到溶解有待测药物的钙缓冲液。将培养孔中的染料吸尽、弃去，用新配置的钙缓冲液清洗培养孔，然后向培养孔中加入50μL溶解有待测药物的钙缓冲液，放入荧光检测仪中，自放入荧光检测仪中起，第15秒时加入25μL溶解有已知激动剂(GPR17激动剂MDL 29951，Santa Cruz Bio公司；重组人M-CSF蛋白，216-MC-025，R&D公司)的钙缓冲液，525nm波长处测定荧光强度。
以上实验步骤的测试原理如下：通过建立具有靶向受体的细胞系，使目标受体被激活后能引起Gal6蛋白的活化，进而激活磷脂酶C(PLC)产生IP3和DAG，IP3可与细胞内质网和线粒体上的IP3受体结合，从而引起细胞内钙离子的释放。因此，测定细胞内钙离子浓度的变化可作为检测目标受体活化状态的方法。Fluo-4/AM是一种钙荧光探针指示剂，用来测量钙离子，作为非极性脂溶性的化合物，进入细胞后在细胞脂解酶的作用下，AM基团解离，释放出Fluo-4。因为Fluo-4是极性分子，不易通过脂质双分子细胞膜，它可使Fluo-4保留在细胞内，随后可以通过测量被激发的荧光强度来反应Gal6蛋白被激活的水平。如果筛选的化合物能够激活目标受体，则可以使钙离子反应升高，反之则使钙离子反应降低。
以上实验步骤的检测结果如表1所示，从表中可以看出，两种阳性对照分别发挥其正常的GPR17和CSFR1的活性抑制作用，而本发明中两种化合物在低浓度下，显示出较强的GPR17和CSFR1的结合和抑制活性。
表1 GPR17和CSFR1抑制活性细胞测试实验
实施例2 GPR17和CSFR1抑制小鼠小胶质细胞活化实验
为了测试测试本发明两类化合物的体内抑制小胶质细胞活化的功能，以下进行抑制小鼠小胶质细胞活化实验。
以C57BL/6J小鼠为实验对象，构建小鼠听力损伤模型。具体是将小鼠暴露于高频噪音中处理2小时。同时设置对照组和听力损伤组作为对照。对照组为正常小鼠。小鼠听力损伤模型构建完成后，化合物I组、化合物II组、Montelukast组和PLX3397组分别腹腔注射相应的实施例1所用的4种化合物，听力损伤组注射等量的PBS溶液，检测小鼠皮质小胶质细胞形态学变化。取小鼠脑组织制备冰冻切片，使用IBA1抗体及相应二抗进行免疫荧光染色。封片后进行形态学观察和统计分析。
以上实验步骤的测试原理如下：听力损伤导致小鼠听觉皮层小胶质细胞活化，当使用具有抑制小胶质细胞活化的功能的化合物治疗后，可减少听力皮层活化小胶质细胞。
表2为不同化合物对小胶质细胞形态的影响结果，表2中，小胶质细胞形态变化的含义是小胶质细胞胞体面积在小胶质细胞整体所占面积中的百分比，小胶质细胞形态变化数值越大说明细胞越可能处于活化状态。结果证实听力损伤小鼠听觉皮层小胶质细胞被活化，与文献报道一致。本实验中阳性对照药物发挥其抑制小胶质细胞活化的作用，而本发明中的两种化合物也显示出较强的抑制听觉皮质小胶质细胞活化作用。
表2不同化合物对小胶质细胞形态的影响结果
实施例3 GPR17和CSFR1抑制小鼠皮质脱髓鞘样变
为了测试本发明两类化合物对的体内抑制小鼠皮质脱髓鞘样变的功能，以下进行相应实验。
以C57BL/6J小鼠为实验对象，按照实施例2的方法构建小鼠听力损伤模型。同时设置对照组和听力损伤组作为对照。对照组为正常小鼠。小鼠听力损伤模型构建完成后，化合物I组、化合物II组、Montelukast组和PLX3397组分别腹腔注射相应的实施例1所用的4种化合物，听力损伤组注射等量的PBS溶液，检测小鼠皮质髓鞘荧光染色强度变化。取小鼠脑组织制备冰冻切片，使用MBP抗体及相应二抗进行免疫荧光染色。封片后进行形态学观察和统计分析。
以上实验步骤的测试原理如下：听力损伤导致小鼠听觉皮层神经元髓鞘保护减少，当使用具有抑制小胶质细胞活化的功能的化合物治疗后，可减少听力皮层神经元髓鞘丢失。
表3为不同化合物对髓鞘染色荧光强度(MBP)的影响结果，图1a-d依次为对照组、听力损伤组、化合物I组、化合物II组的小鼠听觉皮层神经元髓鞘荧光测试结果。结果表明，听力损伤小鼠听觉皮层神经元细胞髓鞘丢失明显。本实验中阳性对照药物发挥其抑制神经元髓鞘丢失的作用，而本发明中两种化合物也显示出较强的抑制听觉皮质神经元髓鞘减少作用。
表3不同化合物对髓鞘染色荧光强度(MBP)的影响结果
以上仅是本发明的优选实施方式，并不用于限制本发明，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明技术原理的前提下，还可以做出若干改进和变型，这些改进和变型也应视为本发明的保护范围。
Claims (10)
1.式(I)和式(II)所示的化合物中的至少一种在制备GPR17和/或CSFR1受体抑制剂中的应用：
其中，A1选自NH、S或O；
A2选自C、N、S或O；
R1、R2和R3分别独立地选自氢、卤素、氰基、叠氮基、硝基或C1-C6烷氧基羰基氨基；
其中，A选自氢、卤素、氰基、叠氮基、硝基或酰胺键；
R5和R6分别独立地选自氢、卤素、氰基、叠氮基、硝基或戊唑基。
2.根据权利要求1所述的应用，其特征在于，式(I)所示的化合物包括以下结构式：
3.根据权利要求1所述的应用，其特征在于，式(II)所示的化合物包括以下结构式：
4.根据权利要求1-3中任一项所述的应用，其特征在于：式(I)和式(II)所示的化合物中的至少一种用于制备GPR17和CSFR1受体抑制剂。
5.根据权利要求4所述的应用，其特征在于：所述GPR17和/或CSFR1受体抑制剂用于制备治疗和/或预防神经退行性疾病的药物。
6.根据权利要求5所述的应用，其特征在于：所述神经退行性疾病由抑制性神经元损伤引起，所述神经退行性疾病包括多发性硬化症、阿尔茨海默氏病、痴呆、噪音致耳聋引发的继发性耳鸣、听觉过敏、偏头痛和神经传入缺失引发的神经痛中的一种或几种。
7.根据权利要求4所述的应用，其特征在于：所述GPR17受体抑制剂用于制备治疗和/或预防GPR17介导的髓鞘形成障碍相关疾病的药物。
8.根据权利要求7所述的应用，其特征在于：所述GPR17介导的髓鞘形成障碍相关疾病包括多发性硬化症、阿尔茨海默氏病、痴呆、听觉过敏、偏头痛和噪音致耳聋引发的继发性耳鸣中的一种或几种。
9.根据权利要求4所述的应用，其特征在于：所述CSFR1受体抑制剂用于制备治疗和/或预防因小胶质细胞异常活化导致的疾病。
10.根据权利要求9所述的应用，其特征在于：所述因小胶质细胞异常活化导致的疾病包括多发性硬化症、听觉过敏、偏头痛、噪音致耳聋引发的继发性耳鸣以及神经传入缺失引发的神经痛中的一种或几种。
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| CN116440133A (zh) * | 2023-04-01 | 2023-07-18 | 苏州安康盟医疗科技有限公司 | 化合物在制备用于治疗和/或预防星形胶质细胞损伤的药物中的应用 |
| EP4556019A4 (en) * | 2022-08-19 | 2025-12-03 | Ushio Electric Inc | ANTIGEN COMPOSITION, COMPOSITION FOR THE EXPRESSION OF AN ANTIGEN, AND ANTIBODY COMPOSITION |
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Cited By (3)
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| CN115957311A (zh) * | 2023-01-06 | 2023-04-14 | 南通大学附属医院 | 组蛋白甲基转移酶ezh2在促视神经髓鞘再生药物中的应用 |
| CN116440133A (zh) * | 2023-04-01 | 2023-07-18 | 苏州安康盟医疗科技有限公司 | 化合物在制备用于治疗和/或预防星形胶质细胞损伤的药物中的应用 |
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