3-{4-[2-({6-氨基-9-[(2R,3R,4S,5S)-5-(乙基氨基甲酰)-3,4-二羟基四氢-2-呋喃基]-9H-嘌呤-2-基}氨基)乙基]苯基}丙酸盐酸盐(1:1) | 124431-80-7

• 物质功能分类: 生物化工 - 抑制剂 - G蛋白偶联受体(GPCR & G Protein)
• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 中文名称: 3-{4-[2-({6-氨基-9-[(2R,3R,4S,5S)-5-(乙基氨基甲酰)-3,4-二羟基四氢-2-呋喃基]-9H-嘌呤-2-基}氨基)乙基]苯基}丙酸盐酸盐(1:1)
• 中文别名: CGS21680盐酸盐；4-[2-[[6-氨基-9-(N-乙基-β-D-呋喃核糖酰胺基)-9H-嘌呤-2-基]氨基]乙基]苯丙酸盐酸盐；CGS21680HCL
• 英文名称: 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride
• 英文别名: CGS 21680；2-(p-(2-carboxyethyl)phenethyl)amino-5′-N-ethylcarboxamidoadenosine hydrochloride；CGS 21680 hydrochloride；CGS 21680A；4-[2-[[6-amino-9-(N-ethyl-β-D-ribofuranuronamidosyl)-9H-purin-2-yl] amino]ethyl]benzenepropanoic acid hydrochloride；3-[4-[2-[[6-amino-9-[(2R,3R,4S,5S)-5-(ethylcarbamoyl)-3,4-dihydroxyoxolan-2-yl]purin-2-yl]amino]ethyl]phenyl]propanoic acid;hydron;chloride
• CAS: 124431-80-7
• 化学式: C₂₃H₂₉N₇O₆*ClH
• 分子量: 535.987
• InChiKey: QPHVMNOEKKJYJO-MJWSIIAUSA-N

物化性质

• 熔点：
  204-206°C
• 溶解度：
  可溶于DMSO（略微加热）、甲醇（略微加热）

计算性质

• 辛醇/水分配系数(LogP)：
  0.26
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  198
• 氢给体数：
  7
• 氢受体数：
  11

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335
• 储存条件：
  | 冰箱 |

制备方法与用途

生物活性 CGS 21680 HCl是一种adenosine A2 receptor激动剂，Ki为27 nM，比作用于A1受体选择性高140倍。

体外研究 CGS 21680 HCl是一种腺苷酸A2受体激动剂，IC50是22 nM，选择性比A1受体高140倍。在离体大鼠心脏灌流模型中，CGS 21680显著增加冠状动脉血流，ED25值为1.8 nM。CGS 21680以高亲和性(Kd = 15.5 nM)结合腺苷酸A2受体，对单个识别位点的结合具有饱和性(表观最大结合量=375 fmol/mg蛋白质)。

在海马切片中，CGS 21680对前突触和后突触电生理学活性具有较弱的激动剂效应（假定Al受体介导的结果），在激活cAMP形成方面不起作用（假定A2介导的响应）。在纹状体切片中，CGS 21680显著激活cAMP形成，EC50为110 nM，但对抑制电刺激诱导的多巴胺释放不起作用。CGS 21680A是盐酸盐形式，CGS 21680C是CGS 21680的钠盐。

体内研究 CGS 21680A在10毫克/千克剂量下对自发性高血压的大鼠口服有效，有效时间达24小时。CGS 21680A引起大鼠瞬时的心率增加（约60分钟）。对于大鼠大脑皮层神经元，CGS 21680是一种有效的乙酰胆碱和谷氨酸盐受体的镇静剂。

靶点

• Adenosine A2 receptor (in rat brain tissue): 22 nM

---

以上为润色后的文本。

反应信息

• 作为反应物：
  描述：

  3-{4-[2-({6-氨基-9-[(2R,3R,4S,5S)-5-(乙基氨基甲酰)-3,4-二羟基四氢-2-呋喃基]-9H-嘌呤-2-基}氨基)乙基]苯基}丙酸盐酸盐(1:1) 在 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成
  参考文献：
  名称：

  Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models

  摘要：

  摘要 骨质流失是一种常见的医学问题，虽然可以用现有疗法治疗，但其中一些疗法具有严重的副作用。我们之前已经证明，选择性 A2A 腺苷受体激动剂 CGS21680 可预防骨质流失，但其靶向毒性（低血压、心动过速）和频繁的给药要求使其无法应用于临床。因此，我们开发了一种新型阿仑膦酸盐-CGS21680共轭物（MRS7216），将激动剂靶向作用于骨质，使其在骨质中长期存在，从而减少给药频率并减轻副作用。MRS7216 由 CGS21680 合成，方法是在碱性条件下依次活化羧酸分子并与适当的氨基酸（PEG、阿仑膦酸）反应。MRS7216在患有骨质疏松症（OP）的C57BL/6J（WT）小鼠和患有磨损颗粒诱导的炎性骨溶解症（OL）的WT或A2A KO小鼠身上进行了测试。小鼠每周接受一次 MRS7216（10 毫克/千克）治疗。使用钙素/茜素红进行体内标记后研究骨形成，并进行μCT和组织学分析。此外，还使用髋关节置换术后丢弃的骨髓培养了人类原发性成骨细胞和破骨细胞。受体结合研究表明，MRS7216 能有效结合 A2A 腺苷受体。与药物或阿仑膦酸钠处理的小鼠相比，MRS7216 处理的 OP 和 OL 小鼠有显著的新骨形成，骨质流失减少。组织学分析表明，在小鼠模型中，MRS7216 治疗可显著减少破骨细胞数量，增加成骨细胞数量。有趣的是，该化合物抑制了培养人破骨细胞的分化，刺激了成骨细胞的分化，这表明 MRS7216 共轭物是治疗骨质疏松症和骨溶解的一种新型疗法。

  DOI：

  10.1186/s13075-022-02961-0
• 作为产物：
  描述：

  2-氯-2,3-o-异亚丙基腺苷酸-5-n-乙基羧酰胺 在 盐酸 作用下， 反应 4.0h， 生成 3-{4-[2-({6-氨基-9-[(2R,3R,4S,5S)-5-(乙基氨基甲酰)-3,4-二羟基四氢-2-呋喃基]-9H-嘌呤-2-基}氨基)乙基]苯基}丙酸盐酸盐(1:1)
  参考文献：
  名称：

  2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands

  摘要：

  The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.

  DOI：

  10.1021/jm00169a015

文献信息

• DENDRIMER CONJUGATES OF AGONISTS AND ANTAGONISTS OF THE GPCR SUPERFAMILY
  申请人：Jacobson Kenneth A.

  公开号：US20090012035A1

  公开（公告）日：2009-01-08

  Disclosed are conjugates comprising a dendrimer and a ligand, which is a functionalized congener of an agonist or antagonist of a receptor of the G-protein coupled receptor (GPCR) superfamily, for example, wherein the functionalized congener is an A 1 adenosine receptor agonist having a purine nucleoside moiety and a functional group at the N 6 position of the purine nucleoside moiety, wherein the functional group has the formula (I): N 6 H—Ar 1 —CH 2 —C(═O)NH—R 1 (I), wherein Ar 1 and R 1 as defined herein. Also disclosed are pharmaceutical compositions, methods of treating various diseases, and a diagnostic method employing such conjugates.

  本文披露了包含树状聚合物和配体的共轭物，其中配体是G-蛋白偶联受体（GPCR）超家族受体的激动剂或拮抗剂的官能化同系物，例如，其中官能化同系物是具有嘌呤核苷酸基团和在嘌呤核苷酸基团的N6位置上具有官能基的A1腺苷受体激动剂，其中官能基具有以下结构式（I）：N6H—Ar1—CH2—C(═O)NH—R1（I），其中Ar1和R1如本文所定义。还披露了包括制药组合物、治疗各种疾病的方法以及使用这种共轭物的诊断方法。
• An Fc Domain Protein–Small Molecule Conjugate as an Enhanced Immunomodulator
  作者：Meng-Jung Chiang、Marc A. Holbert、Jay H. Kalin、Young-Hoon Ahn、John Giddens、Mohammed N. Amin、Martin S. Taylor、Samuel L. Collins、Yee Chan-Li、Adam Waickman、Po-Yuan Hsiao、David Bolduc、Daniel J. Leahy、Maureen R. Horton、Lai-Xi Wang、Jonathan D. Powell、Philip A. Cole

  DOI：10.1021/ja5006674

  日期：2014.3.5

  Proteins as well as small molecules have demonstrated success as therapeutic agents, but their pharmacologic properties sometimes fall short against particular drug targets. Although the adenosine 2a receptor (A(2A)R) has been identified as a promising target for immunotherapy, small molecule A(2A)R agonists have suffered from short pharmacokinetic half-lives and the potential for toxicity by modulating nonimmune pathways. To overcome these limitations, we have tethered the AR agonist CGS-21680 to the immunoglobulin Fc domain using expressed protein ligation with Sf9 cell secreted protein. The protein small molecule conjugate Fc-CGS retained potent Fc receptor and A(2A)R interactions and showed superior properties as a therapeutic for the treatment of a mouse model of autoimmune pneumonitis. This approach may provide a general strategy for optimizing small molecule therapeutics.
• 2-(Arylalkylamino)adenosin-5'-uronamides: a new class of highly selective adenosine A2 receptor ligands
  作者：Alan J. Hutchison、Michael Williams、Reynalda De Jesus、Rina Yokoyama、Howard H. Oei、Geetha R. Ghai、Randy L. Webb、Harry C. Zoganas、George A. Stone、Michael F. Jarvis

  DOI：10.1021/jm00169a015

  日期：1990.7

  The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.
• Novel alendronate-CGS21680 conjugate reduces bone resorption and induces new bone formation in post-menopausal osteoporosis and inflammatory osteolysis mouse models
  作者：Ane Larrañaga-Vera、Kiran S. Toti、James S. Flatow、Alexandra J. Haraczy、Eugene Warnick、Harsha Rao、Zhan-Guo Gao、Sarah M. Sussman、Aranzazu Mediero、Philipp Leucht、Kenneth A. Jacobson、Bruce N. Cronstein

  DOI：10.1186/s13075-022-02961-0

  日期：——

  Loss of bone is a common medical problem and, while it can be treated with available therapies, some of these therapies have critical side effects. We have previously demonstrated that CGS21680, a selective A_2A adenosine receptor agonist, prevents bone loss, but its on-target toxicities (hypotension, tachycardia) and frequent dosing requirements make it unusable in the clinic. We therefore generated a novel alendronate-CGS21680 conjugate (MRS7216), to target the agonist to bone where it remains for long periods thereby diminishing the frequency of administration and curtailing side effects. MRS7216 was synthesized from CGS21680 by sequential activation of the carboxylic acid moiety and reacting with an appropriate amino acid (PEG, alendronic acid) under basic conditions. MRS7216 was tested on C57BL/6J (WT) mice with established osteoporosis (OP) and WT or A2A KO mice with wear particle-induced inflammatory osteolysis (OL). Mice were treated weekly with MRS7216 (10mg/kg). Bone formation was studied after in vivo labeling with calcein/Alizarin Red, and μCT and histology analyses were performed. In addition, human primary osteoblasts and osteoclasts were cultured using bone marrow discarded after hip replacement. Receptor binding studies demonstrate that MRS7216 efficiently binds the A2A adenosine receptor. MRS7216-treated OP and OL mice had significant new bone formation and reduced bone loss compared to vehicle or alendronate-treated mice. Histological analysis showed that MRS7216 treatment significantly reduced osteoclast number and increased osteoblast number in murine models. Interestingly, cultured human osteoclast differentiation was inhibited, and osteoblast differentiation was stimulated by the compound indicating that MRS7216 conjugates represent a novel therapeutic approach to treat osteoporosis and osteolysis.

  摘要 骨质流失是一种常见的医学问题，虽然可以用现有疗法治疗，但其中一些疗法具有严重的副作用。我们之前已经证明，选择性 A2A 腺苷受体激动剂 CGS21680 可预防骨质流失，但其靶向毒性（低血压、心动过速）和频繁的给药要求使其无法应用于临床。因此，我们开发了一种新型阿仑膦酸盐-CGS21680共轭物（MRS7216），将激动剂靶向作用于骨质，使其在骨质中长期存在，从而减少给药频率并减轻副作用。MRS7216 由 CGS21680 合成，方法是在碱性条件下依次活化羧酸分子并与适当的氨基酸（PEG、阿仑膦酸）反应。MRS7216在患有骨质疏松症（OP）的C57BL/6J（WT）小鼠和患有磨损颗粒诱导的炎性骨溶解症（OL）的WT或A2A KO小鼠身上进行了测试。小鼠每周接受一次 MRS7216（10 毫克/千克）治疗。使用钙素/茜素红进行体内标记后研究骨形成，并进行μCT和组织学分析。此外，还使用髋关节置换术后丢弃的骨髓培养了人类原发性成骨细胞和破骨细胞。受体结合研究表明，MRS7216 能有效结合 A2A 腺苷受体。与药物或阿仑膦酸钠处理的小鼠相比，MRS7216 处理的 OP 和 OL 小鼠有显著的新骨形成，骨质流失减少。组织学分析表明，在小鼠模型中，MRS7216 治疗可显著减少破骨细胞数量，增加成骨细胞数量。有趣的是，该化合物抑制了培养人破骨细胞的分化，刺激了成骨细胞的分化，这表明 MRS7216 共轭物是治疗骨质疏松症和骨溶解的一种新型疗法。