2,2',2''-(10-(2-((3-((3-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid | 1613265-38-5

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2,2',2''-(10-(2-((3-((3-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid
• 英文别名: IPN01087；Zalsenertant Tetraxetan；2-[[5-(2,6-dimethoxyphenyl)-1-[4-[methyl-[3-[methyl-[3-[methyl-[2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetrazacyclododec-1-yl]acetyl]amino]propyl]amino]propyl]carbamoyl]-2-propan-2-ylphenyl]pyrazole-3-carbonyl]amino]adamantane-2-carboxylic acid
• CAS: 1613265-38-5
• 化学式: C₅₈H₈₄N₁₀O₁₃
• 分子量: 1129.36
• InChiKey: NQKDJWKHSVVCRZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -4.7
• 重原子数：
  81
• 可旋转键数：
  25
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  271
• 氢给体数：
  5
• 氢受体数：
  19

反应信息

• 作为反应物：
  描述：

  lutetium(III) chloride 、 2,2',2''-(10-(2-((3-((3-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid 在 ammonium acetate 作用下， 以 aq. buffer 为溶剂， 生成 ⁷⁷Lu-IPN01087
  参考文献：
  名称：

  WO2022/266354

  摘要：

  公开号：
• 作为产物：
  描述：

  2-({[1-(4-bromo-2-isopropylphenyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-3-yl]carbonyl}amino)adamantane-2-carboxylic acid 在 trans-di(μ-acetato)bis[o-(di-o-tolylphosphino)benzyl]dipalladium(II) 、 O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 、 tri tert-butylphosphoniumtetrafluoroborate 作用下， 以 1,4-二氧六环 、 二甲基亚砜 为溶剂， 反应 0.5h， 生成 2,2',2''-(10-(2-((3-((3-(4-(3-((2-carboxyadamantan-2-yl)carbamoyl)-5-(2,6-dimethoxyphenyl)-1H-pyrazol-1-yl)-3-isopropyl-N-methylbenzamido)propyl)(methyl)amino)propyl)(methyl)amino)-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid
  参考文献：
  名称：

  10.1007/s00259-024-06754-2

  摘要：

  DOI：

  10.1007/s00259-024-06754-2

文献信息

• Neurotensin receptor ligands
  申请人：3B Pharmaceuticals GmbH

  公开号：EP2740726A1

  公开（公告）日：2014-06-11

  The present invention is related to neurotensin receptor antagonists of formula (I): wherein R1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2-adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9-carboxylic acid; R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkylmethyl, halogen, nitro and trifluoromethyl; ALK is (C2-C5)alkylidene; R3, R4 and R5 are each and independently selected from the group consisting of hydrogen and (C1-C4)alkyl under the proviso that one of R3, R4 and R5 is of the following formula (II) wherein ALK' is (C2-C5)alkylidene; R6 is selected from the group consisting of hydrogen and (C1-C4)alkyl; and R7 is selected from the group comprising H, Acceptor, -[Acceptor-Effector], -[Linker-Acceptor], and -[Linker-Acceptor-Effector], wherein Acceptor is a moiety which mediates linking of an Effector to the N atom of formula (II) or which mediates linking of the Effector to the Linker, Effector is selected from the group comprising a diagnostically active agent and a therapeutically active agent, Linker is a moiety which links the Acceptor to the N atom of formula (II), -[Acceptor-Effector] is a moiety where the Effector is complexed or covalently bound to the Acceptor, -[Linker-Acceptor] is a moiety where the Linker is conjugated to the Acceptor, and -[Linker-Acceptor-Effector] is a moiety where the Linker is conjugated to the Acceptor, whereby the Effector is complexed or covalently bound to the Acceptor; or a pharmacologically acceptable salt, solvate or hydrate thereof.

  本发明涉及公式(I)的神经肽受体拮抗剂：其中R1选自氢、甲基和环丙基；AA-COOH是选自2-氨基-2-脱氢肌酸、环己甘氨酸和9-氨基-双环[3.3.1]壬烷-9-羧酸的氨基酸；R2选自(C1-C6)烷基、(C3-C8)环烷基、(C3-C8)环烷基甲基、卤素、硝基和三氟甲基；ALK是(C2-C5)烷基亚烷基；R3、R4和R5分别且独立地选自氢和(C1-C4)烷基，但是R3、R4和R5中的一个符合以下公式(II)：其中ALK'是(C2-C5)烷基亚烷基；R6选自氢和(C1-C4)烷基；R7选自包括H、受体、-[受体-效应子]、-[连接剂-受体]和-[连接剂-受体-效应子]的群，其中受体是介导将效应子连接到公式(II)的N原子的基团或将效应子连接到连接剂的基团，效应子选自包括诊断活性剂和治疗活性剂的群，连接剂是将受体连接到公式(II)的N原子的基团，-[受体-效应子]是效应子与受体形成络合物或共价结合的基团，-[连接剂-受体]是连接剂与受体结合的基团，-[连接剂-受体-效应子]是连接剂与受体结合的基团，效应子与受体形成络合物或共价结合；或其药理学上可接受的盐、溶剂或水合物。
• Examination of Charge Modifications of an Endolysosomal Trapping Inhibitor in an Antagonistic NTSR1-Targeted Construct for Colon Cancer
  作者：Wei Fan、Wenting Zhang、Sadie Allen、Sameer Alshehri、Kathryn M. Muilenburg、Cheng Zheng、Jered C. Garrison

  DOI：10.1021/acs.bioconjchem.2c00214

  日期：2022.7.20

  Many low-molecular weight targeted radiotherapeutics (TRTs) are capable of rapidly achieving exceptional tumor to non-target ratios shortly after administration. However, the low tumor residence time of many TRTs limits therapeutic dose delivery and has become the Achilles heel to their clinical translation. To combat the tumor efflux of these otherwise promising agents, we have previously presented a strategy of equipping low-molecular weight TRTs with irreversible cysteine cathepsin inhibitors (e.g., E-64 analogues). These inhibitors are capable of forming irreversible adducts with cysteine proteases within the endolysosomal compartments of cells. Using these endolysosomal trapping agents (ETs), the receptor-targeted constructs are able to increase tumor retention and, thus, deliverable therapeutic doses. In this study, we examine this approach in the development of agents targeting the neurotensin receptor subtype 1 (NTSR1), a receptor overexpressed in numerous cancers. Using an antagonistic NTSR1-targeting vector, we explore the impact of charge modification of the ETs on the in vitro and in vivo biological performance of the constructs using HT-29 colon cancer models. Four ETs (based on the epoxysuccinyl peptide E-64) with various charge states were synthesized and incorporated into the structures of the NTSR1-targeted antagonist. These four 177Lu-labeled, ET-enhanced, NTSR1-targeted agents (177Lu-NA-ET1-4), along with the structurally analogous 177Lu-3BP-227, currently in clinical trials, underwent a battery of in vitro assays using HT-29 xenograft colon cancer cells to examine their NTSR1 binding, internalization and efflux, inhibition, and adduct formation properties. The biodistribution profile of these constructs was studied in an HT-29 mouse model. Charge modification of the terminal carboxylic acid and arginine of the ETs had deleterious effects on inhibition kinetics and in vitro adduct formation. Contrastingly, deletion of the arginine resulted in a modest increase in inhibition kinetics. Incorporation of ETs into the NTSR1-targeted agents was well-tolerated with minimal impact on the in vivo NTSR1 targeting but resulted in increased renal uptake. This study demonstrates that the ETs can be successfully incorporated into antagonistic NTSR1-targeted constructs without compromising their adduct formation capabilities. Based on these results, further exploration of the endolysosomal trapping approach is warranted in NTSR1- and other receptor-targeted antagonistic constructs.

  许多低分子量靶向放射治疗药物（TRTs）能够在给药后不久迅速达到优异的肿瘤与非靶点比率。然而，许多靶向放射治疗药物的肿瘤停留时间较短，这限制了治疗剂量的传递，成为其临床转化的致命弱点。为了解决这些本来很有前景的药物的肿瘤外流问题，我们之前提出了一种在低分子量 TRTs 中加入不可逆半胱氨酸酪蛋白酶抑制剂（如 E-64 类似物）的策略。这些抑制剂能够与细胞内溶酶体内的半胱氨酸蛋白酶形成不可逆的加合物。利用这些内溶酶体捕获剂（ETs），受体靶向构建物能够增加肿瘤保留率，从而提高可递送的治疗剂量。在本研究中，我们研究了这种针对神经紧张素受体亚型 1（NTSR1）的药物开发方法，NTSR1 是一种在多种癌症中过度表达的受体。我们使用一种拮抗 NTSR1 靶向载体，利用 HT-29 结肠癌模型探讨了 ET 的电荷修饰对构建体的体外和体内生物学性能的影响。我们合成了四种具有不同电荷状态的 ET（基于环氧琥珀酰肽 E-64），并将其纳入 NTSR1 靶向拮抗剂的结构中。这四种 177Lu 标记、ET 增强、NTSR1 靶向药剂（177Lu-NA-ET1-4）以及目前正在进行临床试验的结构类似的 177Lu-3BP-227，使用 HT-29 异种移植结肠癌细胞进行了一系列体外试验，以检查它们的 NTSR1 结合、内化和外流、抑制和加合物形成特性。在 HT-29 小鼠模型中研究了这些构建物的生物分布特征。对 ETs 的末端羧酸和精氨酸进行电荷修饰会对抑制动力学和体外加合物形成产生有害影响。相反，精氨酸的缺失导致抑制动力学略有增加。在 NTSR1 靶向药物中掺入 ETs 的耐受性良好，对体内 NTSR1 靶向的影响极小，但会导致肾摄取量增加。这项研究表明，ETs 可以成功地加入到拮抗 NTSR1 靶向构建物中，而不会影响其加合物形成能力。基于这些结果，有必要在 NTSR1 和其他受体靶向拮抗构建物中进一步探索溶酶体内捕获方法。
• Conjugate comprising a neurotensin receptor ligand and use thereof
  申请人：3B PHARMACEUTICALS GMBH

  公开号：US10799605B2

  公开（公告）日：2020-10-13

  The present invention is related to a conjugate comprising a structure of general formula (1) [TM1]-[AD1]-[LM]-[AD2]-[TM2] (1), wherein TM1 is a first targeting moiety, wherein the first targeting moiety is capable of binding to a first target, AD1 is a first adapter moiety or is absent, LM is a linker moiety or is absent, AD2 is a second adapter moiety or is absent, and TM2 is a second targeting moiety, wherein the second targeting moiety is capable of binding to a second target; wherein the first targeting moiety and/or the second targeting moiety is a compound of formula (2): wherein R1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2 adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9 carboxylic acid; R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3C8)cycloalkylmethyl, halogen, nitro and trifluoromethyl; ALK′ is (C2-C5)alkylidene; R3, R4 and R5 are each and independently selected from the group consisting of hydrogen and (C1-C4)alkyl under the proviso that one of R3, R4 and R5 is of the following formula (3) wherein ALK′ is (C2-C5)alkylidene; R6 is selected from the group consisting of hydrogen and (C1-C4)alkyl; and R7 is a bond; or a pharmacologically acceptable salt, solvate or hydrate thereof.

  本发明涉及一种包含通式（1）[TM1]-[AD1]-[LM]-[AD2]-[TM2]（1）结构的共轭物，其中 TM1 是第一靶向分子，其中第一靶向分子能够与第一靶点结合、AD1 是第一适配基团或不存在，LM 是连接基团或不存在，AD2 是第二适配基团或不存在，TM2 是第二靶向基团，其中第二靶向基团能够与第二靶点结合；其中第一靶向分子和/或第二靶向分子是式 (2) 的化合物：其中 R1 选自由氢、甲基和环丙基甲基组成的组； AA-COOH 是选自由 2-氨基-2-金刚烷羧酸、环己基甘氨酸和 9-氨基-双环[3.3.R2选自由(C1-C6)烷基、(C3-C8)环烷基、(C3C8)环烷基甲基、卤素、硝基和三氟甲基组成的组；ALK′为(C2-C5)亚烷基；R3、R4 和 R5 各自独立地选自氢和(C1-C4)烷基组成的组，但 R3、R4 和 R5 中的一个应符合下式(3)，其中 ALK′为(C2-C5)亚烷基；R6 选自氢和(C1-C4)烷基组成的组；R7 为键；或其药理学上可接受的盐、溶液或水合物。
• NEUROTENSIN RECEPTOR LIGANDS
  申请人：3B Pharmaceuticals GmbH

  公开号：EP2928870B1

  公开（公告）日：2020-04-08
• CONJUGATE COMPRISING A NEUROTENSIN RECEPTOR LIGAND AND USE THEREOF
  申请人：3B PHARMACEUTICALS GMBH

  公开号：US20170119913A1

  公开（公告）日：2017-05-04

  The present invention is related to a conjugate comprising a structure of general formula (1) [TM1]-[AD1]-[LM]-[AD2]-[TM2] (1), wherein TM1 is a first targeting moiety, wherein the first targeting moiety is capable of binding to a first target, AD1 is a first adapter moiety or is absent, LM is a linker moiety or is absent, AD2 is a second adapter moiety or is absent, and TM2 is a second targeting moiety, wherein the second targeting moiety is capable of binding to a second target; wherein the first targeting moiety and/or the second targeting moiety is a compound of formula (2): wherein R 1 is selected from the group consisting of hydrogen, methyl and cyclopropylmethyl; AA-COOH is an amino acid selected from the group consisting of 2-amino-2 adamantane carboxylic acid, cyclohexylglycine and 9-amino-bicyclo[3.3.1]nonane-9 carboxylic acid; R 2 is selected from the group consisting of (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, (C 3 C 8 )cycloalkylmethyl, halogen, nitro and trifluoromethyl; ALK′ is (C 2 -C 5 )alkylidene; R 3 , R 4 and R 5 are each and independently selected from the group consisting of hydrogen and (C 1 -C 4 )alkyl under the proviso that one of R 3 , R 4 and R 5 is of the following formula (3) wherein ALK′ is (C 2 -C 5 )alkylidene; R 6 is selected from the (2) group consisting of hydrogen and (C 1 -C 4 )alkyl; and R 7 is a bond; or a pharmacologically acceptable salt, solvate or hydrate thereof.