CN118165073A - 一种fap抑制剂及其制备方法和应用 - Google Patents
一种fap抑制剂及其制备方法和应用 Download PDFInfo
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- CN118165073A CN118165073A CN202410592564.2A CN202410592564A CN118165073A CN 118165073 A CN118165073 A CN 118165073A CN 202410592564 A CN202410592564 A CN 202410592564A CN 118165073 A CN118165073 A CN 118165073A
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- Prior art keywords
- fap
- fap inhibitor
- inhibitor
- pharmaceutically acceptable
- compound
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Abstract
本发明公开了一种FAP抑制剂及其制备方法和应用，所述FAP抑制剂的通式如式（Ⅰ）所示，本发明的新型FAP抑制剂结合相应的放射性元素可以用于FAP阳性相关疾病的诊断和治疗，相比于传统的FAPI放射性药物，所述新型FAP抑制剂在病灶部位摄取率更高、靶与非靶对比度更高，且无明显毒副作用；也可以用于肿瘤（胰腺癌、乳腺癌、卵巢癌、肺癌、结直肠癌、胃癌），心肌梗死，瘢痕形成，骨质疏松、肝、肾和肺纤维化，慢性炎症和破坏性过程（类风湿性关节炎、克罗恩病、动脉粥样硬化斑块、免疫球蛋白相关疾病）等疾病的治疗和诊断。
Description
技术领域
本发明涉及一种FAP抑制剂及其制备方法和应用，属于药物化学&放射性药物领域。
背景技术
成纤维细胞活化蛋白-α（FAP，Fibroblast activation protein-α）是一种具有二肽基肽酶活性和内肽酶活性的II型跨膜丝氨酸蛋白酶。参与细胞外基质降解并参与许多细胞过程，包括组织重塑、纤维化、伤口愈合、炎症和肿瘤生长。在超过90%的上皮性癌组织中，FAP选择性地表达于肿瘤间质中的癌症相关成纤维细胞（CAF）细胞，但在正常组织中很少表达或不表达。CAF的特异性表面标志物FAP参与癌症发生发展过程中的增殖、侵袭、血管生成、上皮向间质转化、干细胞促进、免疫抑制和耐药等过程。因此，FAP成为多种恶性肿瘤的诊断和治疗靶点。
一种基于N-4-quinolinoyl-Gly-(2S)-cyanoPro骨架的强效选择性FAP抑制剂（UAMC1110）为喹啉FAP抑制剂的开发提供了先导。因此，一系列喹啉为基础的芳香族小分子被开发为FAP抑制剂（FAPIs）和诊断或治疗放射性核素标记药物。目前已有多种基于喹啉开发的小分子FAP抑制剂展开临床实验，最高已达临床II期。相比于喹啉FAP抑制剂，一种177Lu标记的新型FAP环肽配体FAP-2286在小鼠模型中取得更优的亲和力，肿瘤滞留效果和更长的体内保留时间，从而表现出更好的治疗效果。
但是目前诊断或治疗放射性核素标记的FAP抑制剂普遍存在体内清除较快，肝肠摄取的问题。因此需要开发一种体内保留时间长、肿瘤靶向性好的核素标记FAP抑制剂，用于癌症诊断与治疗。
Feng-Ting Huang课题组设计的FAPtp（II）作为一类靶向FAP多肽类化合物显像效果差，肿瘤摄取率低，体内代谢动力学性质较差（Rational Design, Pharmacomodulation,and Synthesis of [68Ga]Ga-Alb-FAPtp-01, a Selective Tumor-AssociatedFibroblast Activation Protein Tracer for PET Imaging of Glioma. Lin JJ, etal. ACS Sens. 2021.）。
。
发明内容
发明目的：本发明所要解决的技术问题是提供了一种可用于肿瘤、心肌梗死，瘢痕形成，骨质疏松、肝、肾和肺纤维化，慢性炎症和破坏性过程等疾病的治疗和/或诊断的新型的FAP抑制剂及其制备方法和应用。
技术方案：为解决上述技术问题，本发明提供所述的新型FAP抑制剂为如式（Ⅰ）所示结构及其药学上可接受的盐、水合物、溶剂化合物及放射性元素标记物：
；
其中， R1为氢、甲基；
R2为芳香取代基，包括α-萘甲基、1H-吲哚-3-甲基、苯甲基、4-羟基苯甲基；
X包括-NH-，-CH2O-，-CHNH-，-CH2-；
R3为极性氨基酸；
R4是基于-(CH2)p-的替换结构，其中p是0至16的整数，其中，每个-CH2-单独的用或不用-O-、-NH-、-(CO)-、-NH-(CO)-、-CH(NH2)-或-(CO)-NH-替换；
R5为锝-99m的配位基团，或者配位基团与锝-99m形成锝99mTc（V）、99mTc（III）、99mTc（I）配合物。
其中，R5为HYNIC（6 -肼- 4 -烟酸）、MAG3（巯基乙酰三甘氨酸）。
其中，所述新型FAP抑制剂为下列化合物中的至少一种：
。
本发明还提供了一种新型FAP抑制剂药物组合物。
其中，所述的新型FAP抑制剂药物组合物包含上述的新型FAP抑制剂为活性成分。
本发明还提供了上述的FAP抑制剂或其组合物在制备治疗和/或诊断以FAP阳性为特征的疾病的药物中的应用。
其中，所述以FAP阳性为特征的疾病包括肿瘤，心肌梗死，瘢痕形成，骨质疏松，肝、肾和肺纤维化或慢性炎症中的一种或几种。
本发明所提供的一种新型FAP多肽化合物具有更高的肿瘤摄取，理想的体内分布，满足临床核医学的显像需求。
有益效果：与现有技术相比，本发明具有如下显著优点：
1、本发明的新型FAP抑制剂结合相应的放射性元素可以用于FAP阳性相关疾病的诊断和治疗，相比于传统的FAPI放射性药物，所述新型FAP抑制剂在病灶部位摄取率更高、靶与非靶对比度更高；
2、本发明FAPI抑制剂可以用于肿瘤（胰腺癌、乳腺癌、卵巢癌、肺癌、结直肠癌、胃癌），心肌梗死，瘢痕形成，骨质疏松、肝、肾和肺纤维化，慢性炎症和破坏性过程（类风湿性关节炎、克罗恩病、动脉粥样硬化斑块、免疫球蛋白相关疾病）等疾病的治疗和诊断。
附图说明
图1为化合物1的MS（ESI）谱图；
图2为化合物2的MS（ESI）谱图；
图3为化合物3的MS（ESI）谱图；
图4为化合物4的MS（ESI）谱图；
图5为化合物1在U87MG小鼠体内核素显像图；
图6为化合物1~4在U87MG小鼠离体器官摄取值。
具体实施方式
下面结合附图对本发明的技术方案作进一步说明。
实施例中涉及的试剂来源：
2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯（HATU）、2-(2-(2-氨基乙氧基)乙氧基)乙基氨基甲酸叔丁酯、N-芴甲氧羰基-L-氨基酸、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯（HCTU）、三异丙基硅烷（TIPs）、Fmoc- (4-吡啶基)-L-丙氨酸、4-戊炔酸、三苯基膦三间磺酸钠盐（TPPTS）溶液、三(羟甲基)甲基甘氨酸（Tricine）溶液、化合物a2、a5等试剂均购自上海毕得医药科技股份有限公司。Fmoc-Gly-CTC树脂（货号：230629-44701）、Fmoc-SPPS树脂购自南京肽业生物科技有限公司。
二氯甲烷（DCM）、甲醇（MeOH）、二甲亚砜（DMSO）、甲基叔丁基醚、N,N-二甲基甲酰胺（DMF）、三氟乙酸（TFA）、N,N-二异丙基乙胺（DIEA）、乙腈（ACN）、等常规试剂购自上海麦克林生化科技股份有限公司或者上海阿拉丁生化科技股份有限公司。
实施例中涉及的U87MG荷瘤鼠动物模型：
细胞培养：U87MG细胞系（来自中国科学院上海细胞库）用含10 %（v/v）胎牛血清的DMEM培养基处于37 ℃含5 % CO2培养箱中培养。待细胞长到适宜密度时，吸走培养基，用PBS清洗一遍后，加入适宜体积胰蛋白酶置于培养箱中消化，待细胞不再贴壁时，加入1 ml含胎牛血清的培养基终止消化，随后1000 rpm离心4 min，收集细胞。
荷瘤鼠模型构建：将处于对数增长期的细胞消化至离心管中用适量PBS重悬，用5*10^6细胞数量重悬于生理盐水中，将细胞接种于周龄4-7 W，体重20 g左右Balbc/Nu裸鼠上肢腋下附近。待接种后10-20天即可成瘤。
实施例1化合物1的制备：
合成路线：
。
1、化合物a1的合成：
化合物a1通过常规Fmoc-SPPS多肽固相合成方法得到，其序列为：FmocNH-PEG4-脯氨酸-α-萘基丙氨酸-甘氨酸-COOH。具体方法如下：
（1）树脂溶胀
称取Fmoc-Gly-CTC树脂（500 mg，负载量0.2mmol）加入多肽合成管，加入二氯甲烷（DCM）溶胀20min。抽掉DCM溶液，用N,N-二甲基甲酰胺（DMF）洗涤，抽干；
（2）脱除Fmoc
合成管中加入20%哌啶的DMF溶液，脱保护时间为5min，重复两次。反应结束后用DMF洗涤；
（3）偶联
向合成管中加入氨基酸（0.3mmol，1.5eq）、N,N-二异丙基乙胺（DIEA，0.3mmol，1.5eq）、六氟磷酸酯（HCTU，0.3mmol，1.5eq）和DMF，震荡反应2h，抽掉反应液并用DMF洗涤，然后加入按步骤（2)的方式脱Fmoc，洗净；
（4）根据序列中氨基酸以及侧链连接子的种类重复步骤（2）和（3），直至连接子完成偶联；
（5）切割
将树脂用DCM和甲醇（MeOH）冲洗两遍，再用氮气吹干，加入切割液（TFA：H2O：TIPS=95:5:5，v/v/v）震荡反应3h。反应结束抽滤得到滤液，将滤液中的大部分溶剂旋干，加入10ml甲基叔丁基醚，抽滤，用乙酸乙酯清洗两遍，得到化合物a1（104 mg，收率62%）。
2、化合物a3的合成：
取a1(83.9mg，0.1 mmol)，(S)-4,4-二氟吡咯烷-2-甲腈盐酸盐a2(13.2mg，0.1mmol)溶于5 mL DMF溶液中，加入2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU，57 mg，0.15 mmol)，N-乙基二异丙胺(DIPEA，39 mg，3 mmol),室温反应1.5 h。TLC检测反应完全，浓缩反应液。用少量DCM溶解，湿法上样，DCM/MeOH体系柱层析纯化。
3、化合物a4的合成：
取a3(20 mg，0.02 mmol)溶于1 mL含20 %（v/v）哌啶的DMF溶液中，反应30min。TLC检测反应完全，浓缩反应液。用少量DCM溶解，湿法上样，DCM/MeOH体系柱层析纯化。
4、化合物1的合成：
取a4（5 mg，0.007 mmol），a5（3.1 mg，0.008 mmol，1.2eq）溶于DMF溶液中，加入DIPEA（2.7 µL，0.021mmol），室温反应2 h。TLC检测反应完全，浓缩反应液。采用制备型反相高效液相色谱仪分离纯化（分离条件：Agilent C18柱，9.4x240 mm，5 μm），洗脱梯度如表1所示。
表1 液相洗脱梯度
冷冻干燥得到化合物1。ESI-MS:997.85 [M+H]+。化合物1的结构表征如图1所示。
实施例2化合物2制备：
合成路线：
化合物b1参照实施例1中Fmoc-SPPS多肽固相合成方法得到（合成所用试剂以及仪器均同实施例1），其序列为：FmocNH-PEG4-精氨酸-脯氨酸-α-萘基丙氨酸-甘氨酸-COOH。参照实施例1中的方法（通过等摩尔量的反应投料比，相同的反应时间、温度、后处理过程），最终得到化合物2。ESI-MS: 1153.88[M+H]+。化合物2的结构表征如图2所示。
实施例3 化合物3制备：
合成路线：
化合物c1参照实施例1中Fmoc-SPPS多肽固相合成方法得到（合成所用试剂以及仪器均同实施例1），其序列为：FmocNH-甘氨酸-甘氨酸-甘氨酸-3-羧基吗啉-色氨酸-甘氨酸-COOH。参照实施例1中的方法（通过等摩尔量的反应投料比，相同的反应时间、温度、后处理过程），最终得到化合物3。ESI-MS:983.76 [M+Na]+。化合物3的结构表征如图3所示。
实施例4化合物4制备：
合成路线：
化合物d1参考实施例1中Fmoc-SPPS多肽固相合成方法得到（合成所用试剂以及仪器均同实施例1），其序列为：FmocN-脯氨酸-甘氨酸-脯氨酸-甘氨酸-脯氨酸-苯丙氨酸-甘氨酸-COOH。参照实施例1中的方法（通过等摩尔量的反应投料比，相同的反应时间、温度、后处理过程），最终得到化合物4。ESI-MS: 1008.72[M+H]+。化合物4的结构表征如图4所示。
实施例5 化合物5制备：
合成路线：
化合物e1参考实施例1中Fmoc-SPPS多肽固相合成方法得到（合成所用试剂以及仪器均同实施例1），其序列为：FmocNH-氨基己酸-谷氨酸-脯氨酸-酪氨酸-甘氨酸-COOH。参照实施例1中的方法（通过等摩尔量的反应投料比，相同的反应时间、温度、后处理过程），最终得到化合物5。ESI-MS（estimated）: 959.04[M+H]+。
实施例6 化合物6制备：
合成路线：
化合物f1参考实施例1中Fmoc-SPPS多肽固相合成方法得到（合成所用试剂以及仪器均同实施例1），其序列为：FmocNH-PEG2-精氨酸-2-哌啶酸-色氨酸-丙氨酸-COOH。参照实施例1中的方法（通过等摩尔量的反应投料比，相同的反应时间、温度、后处理过程），最终得到化合物6。ESI-MS（estimated）: 1083.23[M+H]+。
实施例7 化合物7制备：
合成路线：
化合物g1参考实施例1中Fmoc-SPPS多肽固相合成方法得到（合成所用试剂以及仪器均同实施例1），其序列为：FmocNH-氨基己酸-精氨酸-脯氨酸-α-萘基丙氨酸-甘氨酸-COOH。参照实施例1中的方法（通过等摩尔量的反应投料比，相同的反应时间、温度、后处理过程），最终得到化合物7。ESI-MS（estimated）: 1020.17[M+H]+。
实施例8 化合物8制备：
合成路线：
按照实施例1的方法合成a4，将实施例1中的a5按照等摩尔量替换成h4（购自上海毕得医药有限公司），最终得到化合物8。ESI-MS（estimated）: 1006.11[M+H]+。
实施例9 化合物的肿瘤治疗效果检测
取0.2 M的三苯基膦三间磺酸钠盐（TPPTS）溶液以及1 M的三(羟甲基)甲基甘氨酸（Tricine）溶液，在西林瓶取1 μg标记前体（依次为：化合物1、化合物2、化合物3、化合物4）溶解于10 μl的TPPTS溶液和10 μl的Tricine溶液中，加入1 mCi高锝酸钠溶液，用生理盐水定容至100 μl，将溶液转移至西林瓶中。将西林瓶置于100 ℃金属浴中加热20min。加热完毕后，将其冷却置于室温即可得到99mTc标记药物，即99mTc标记的化合物1、化合物2、化合物3、化合物4。
将400 μCi99mTc标记的化合物1溶解于150 μl生理盐水中，通过尾静脉注射入U87MG荷瘤鼠中。分别在注射后0.5 h、1 h、2 h对荷瘤鼠进行SPECT成像，成像过程中用异氟烷保持麻醉。成像完成后用Nucline 3.0软件对文件进行重建得到图像。
如图5所示，化合物1具有肿瘤边缘清晰、肿瘤/背景对比度良好、非靶部位清除快。同样的方法检测化合物2~8，其均具有良好的成像结果。
实施例10
按照实施例9的方法，分别制备100 μCi99mTc标记的化合物1、化合物2、化合物3、化合物4，分别通过尾静脉注射入U87MG荷瘤鼠中（n=3），记录活度测量时间以及注射时间。注射完成后1h，将小鼠通过眼球取血后，颈椎脱臼处死。将小鼠解剖，取心、肝、脾、肺、肾、胃、肠、肌肉、骨骼、脑、肿瘤至于生理盐水中清洗，将离体器官表面水分擦干后，称量质量并记录。将不同活度（0.85 μCi、0.64 μCi、0.425 μCi、0.213 μCi）的高锝酸钠溶液，取至2 mlEP管中（n=3），得到12支标准管，记录活度测量时间。将所有标准管、器官以及血液通过γ-counter测量其counts数（CPM），将γ-counter测量的标准管CPM值通过半衰期校正得到测量时的CPM值，通过建立活度值-CPM值标准曲线，即可将样品测量得到的CPM值转化为活度。摄取值（% ID/g）=样品活度值/注射药物活度值/样品重量*100 %（所有活度值均通过衰减校正为注射时的活度值）。
如图6所示，化合物1~4具有非常高的肿瘤摄取值、肿瘤/肌肉对比度及良好的体内代谢分布。同样的方法检测化合物5~8，其均具有非常高的肿瘤摄取值、肿瘤/肌肉对比度及良好的体内代谢分布。化合物5~8具有相同的设计思路和关键结合部位，通过改变连接子、增加极性氨基酸从而改善体内分布，在同样方法的检测下，能够实现较好的实验结果。
Claims (10)
1.一种FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物，其特征在于，通式如式（Ⅰ）所示：
；
其中，R1为氢、甲基；
R2为芳香取代基，包括α-萘甲基、1H-吲哚-3-甲基、苯甲基、4-羟基苯甲基；
X包括-NH-，-CH2O-，-CHNH-，-CH2-；
R3为极性氨基酸；
R4是基于-(CH2)p-的替换结构，其中p是0至16的整数，其中，每个-CH2-单独的用或不用-O-、-NH-、-(CO)-、-NH-(CO)-、-CH(NH2)-或-(CO)-NH-替换；
R5为锝-99m的配位基团，或者配位基团与锝-99m形成锝99mTc（V）、99mTc（III）、99mTc（I）配合物。
2.根据权利要求1所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物，其特征在于，R2为α-萘甲基，1H-吲哚-3-甲基，苯甲基或4-羟基苯甲基；
R3为精氨酸、谷氨酸或天冬氨酸，数量为0~5。
3.根据权利要求1所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物，其特征在于，R4的替换条件是不相邻的两个-CH2-基团被替换，替换方式为包括使用亲核取代、点击化学、缩合反应或迈克尔加成的方式进行连接。
4.根据权利要求1所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物，其特征在于，R5为6 -肼- 4 -烟酸或巯基乙酰三甘氨酸。
5.根据权利要求1所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物，其特征在于，R5选自：
。
6.根据权利要求1所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物，其特征在于，所述FAP抑制剂如下任一项所示：
。
7.一种制备权利要求1~6任一项所述FAP抑制剂的方法，其特征在于，包括以下步骤：通过Fmoc固相合成方法得到化合物主体；通过缩合反应连接(S)-4,4-二氟吡咯烷-2-甲腈；通过哌啶/DMF溶液脱除保护基；最后通过取代反应与活化的HYNIC或活化的MAG3 连接。
8.一种FAP抑制剂药物组合物，其特征在于，其包含权利要求1~6任一项所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物。
9.一种放射性药物，其特征在于，其包含权利要求1~6任一项所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物。
10.权利要求1~6任一项所述FAP抑制剂及其药学上可接受的盐、水合物或溶剂化合物或权利要求8所述FAP抑制剂药物组合物或权利要求9所述放射性药物在制备治疗和/或诊断以FAP阳性为特征的疾病的药物中的应用。
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