苯基甲基(2S)-2-[[2-[[(2S)-2-氨基-4-甲硫基丁基]二巯基甲基]-3-苯基丙酰基]氨基]-3-苯丙酸酯 | 135949-60-9

• 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
• 中文名称: 苯基甲基(2S)-2-[[2-[[(2S)-2-氨基-4-甲硫基丁基]二巯基甲基]-3-苯基丙酰基]氨基]-3-苯丙酸酯
• 英文名称: RB 101
• 英文别名: benzyl (2S)-2-[[2-[[[(2S)-2-amino-4-methylsulfanylbutyl]disulfanyl]methyl]-3-phenylpropanoyl]amino]-3-phenylpropanoate
• CAS: 135949-60-9
• 化学式: C₃₁H₃₈N₂O₃S₃
• 分子量: 582.852
• InChiKey: QXXMSEVVNUSHKJ-KEKPXRHTSA-N

物化性质

• 沸点：
  757.5±60.0 °C(Predicted)
• 密度：
  1.210±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.7
• 重原子数：
  39
• 可旋转键数：
  18
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  157
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  消旋卡多曲二元酸杂质 在 盐酸 、 1-羟基苯并三唑 、 三乙胺 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 氯仿 为溶剂， 反应 5.0h， 生成 苯基甲基(2S)-2-[[2-[[(2S)-2-氨基-4-甲硫基丁基]二巯基甲基]-3-苯基丙酰基]氨基]-3-苯丙酸酯
  参考文献：
  名称：

  Mixed-inhibitor-prodrug as a new approach toward systemically active inhibitors of enkephalin-degrading enzymes

  摘要：

  In order to evaluate the possible advantages of potentiating the effects of the endogenous enkephalins, to obtain analgesia without the serious drawbacks of morphine, it was essential to design systemically active compounds which inhibit the two metabolizing enzymes, aminopeptidase N (APN) and neutral endopeptidase 24.11 (NEP). A new concept combining the idea of "prodrug" and "mixed inhibitor" was therefore developed. Given the high efficiency of beta-mercaptoalkylamines as APN inhibitors and of N-(mercaptoacyl) amino acids as NEP inhibitors, compounds associating these molecules through disulfide or thioester bonds, which are known to increase lipophilicity and to favor passage across the blood-brain barrier, have been synthesized. An HPLC study indicated that the disulfide bridge was resistant to serum enzymes but was cleaved by brain membrane homogenates, suggesting that the active inhibitors were released in the central nervous system. The validity of the approach was verified by the efficient antinociceptive responses obtained in the hot plate test in mice after iv administration of disulfide-containing inhibitors (ED50s of from 4 to 26 mg/kg on the jump latency time). The analgesic potencies of the "mixed inhibitor-prodrug" RB 101 [H2NCH(CH2CH2SCH3)CH2SSCH2CH(CH2Ph)CONHCH(CH2Ph)COOCH2Ph] after iv administration were three times greater than those of a similar combined dose of its two constitutive moieties. The separation of the two diastereoisomers constituting RB 101 showed that the analgesia has a stereochemical dependence, the (S,S,S)-isomer being more active than the (S,R,S)-isomer. Furthermore, in the tail flick test in the rat, RB 101 gave 38% analgesia at a dose of 80 mg/kg. Due to its high efficiency and its longer pharmacological effect, RB 101 was selected for a complete study of its analgesic properties.

  DOI：

  10.1021/jm00091a016

文献信息

• ANP fragment adjuvant therapy to standard of care (SOC) diuretic treatment
  申请人：MADELEINE PHARMACEUTICALS PTY LTD

  公开号：US10004754B2

  公开（公告）日：2018-06-26

  A therapeutic method for treating and/or preventing diseases and medical conditions typically treated by administering diuretic agents (eg congestive heart failure). The method may comprise, for example, administering to a subject a diuretic agent in combination with vessel dilator (VSDL) or a variant or modified peptide thereof. The administration of the diuretic agent may be a component of a standard of care (SOC) treatment.

  一种治疗方法，用于治疗和/或预防通常通过施用利尿剂治疗的疾病和病症（如充血性心力衰竭）。例如，该方法可包括向受试者施用与血管扩张剂（VSDL）或其变体或修饰肽结合的利尿剂。利尿剂的给药可以是标准治疗（SOC）的组成部分。
• CD20 therapies, CD22 therapies, and combination therapies with a CD19 chimeric antigen receptor (CAR)-expressing cell
  申请人：Novartis AG

  公开号：US10253086B2

  公开（公告）日：2019-04-09

  The invention provides compositions and methods for treating diseases associated with expression of CD19, e.g., by administering a recombinant T cell comprising the CD19 CAR as described herein, in combination with one or more B-cell inhibitors, e.g., inhibitors of one or more of CD10, CD20, CD22, CD34, CD123, FLT-3, ROR1, CD79b, CD179b, or CD79a. The disclosure additionally features novel antigen binding domains and CAR molecules directed to CD20 and CD22, and uses, e.g., as monotherapies or in combination therapies. The invention also provides kits and compositions described herein.

  本发明提供了治疗与CD19表达相关疾病的组合物和方法，例如，通过施用包含本文所述CD19 CAR的重组T细胞与一种或多种B细胞抑制剂，例如，CD10、CD20、CD22、CD34、CD123、FLT-3、ROR1、CD79b、CD179b或CD79a中一种或多种的抑制剂联合使用。此外，本发明还提供了新型抗原结合域和针对 CD20 和 CD22 的 CAR 分子，以及其用途（如作为单一疗法或联合疗法）。本发明还提供了本文所述的试剂盒和组合物。
• Methods for improving the efficacy and expansion of immune cells
  申请人：The Trustees of the University of Pennsylvania

  公开号：US10829735B2

  公开（公告）日：2020-11-10

  The invention provides methods of making immune effector cells (e.g., T cells, NK cells) that can be engineered to express a chimeric antigen receptor (CAR), compositions and reaction mixtures comprising the same, and methods of treatment using the same.

  本发明提供了制造可被设计为表达嵌合抗原受体（CAR）的免疫效应细胞（如T细胞、NK细胞）的方法、包含嵌合抗原受体的组合物和反应混合物，以及使用嵌合抗原受体进行治疗的方法。
• Nucleic acid molecules encoding chimeric antigen receptors comprising a CD20 binding domain
  申请人：Novartis AG

  公开号：US11026976B2

  公开（公告）日：2021-06-08

  The invention provides compositions and methods for treating diseases associated with expression of CD20 or CD22. The invention also relates to chimeric antigen receptor (CAR) specific to CD20 or CD22, vectors encoding the same, and recombinant T or natural killer (NK) cells comprising the CD20 CAR or CD22 CAR. The invention also includes methods of administering a genetically modified T cell or NK cell expressing a CAR that comprises a CD20 or CD22 binding domain.

  本发明提供了治疗与CD20或CD22表达相关疾病的组合物和方法。本发明还涉及特异于 CD20 或 CD22 的嵌合抗原受体（CAR）、编码 CD20 或 CD22 的载体以及包含 CD20 CAR 或 CD22 CAR 的重组 T 细胞或自然杀伤（NK）细胞。本发明还包括施用表达包含 CD20 或 CD22 结合域的 CAR 的转基因 T 细胞或 NK 细胞的方法。
• CD20 THERAPIES, CD22 THERAPIES, AND COMBINATION THERAPIES WITH A CD19 CHIMERIC ANTIGEN RECEPTOR (CAR) - EXPRESSING CELL
  申请人：Novartis AG

  公开号：EP3280729B1

  公开（公告）日：2022-04-27