(1S，2R，3S，4R，5S)-4-[6-[[((3-氯苯基)甲基]氨基]-2-[2-(3,4-二氟苯基)乙炔基]-9H-嘌呤-9-yl]-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-羧酰胺 | 1377273-00-1

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 核苷和核苷酸类似物
• 中文名称: (1S，2R，3S，4R，5S)-4-[6-[[((3-氯苯基)甲基]氨基]-2-[2-(3,4-二氟苯基)乙炔基]-9H-嘌呤-9-yl]-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-羧酰胺
• 英文名称: MRS5698
• 英文别名: (1S,2R,3S,4R,5S)-4-(6-((3-chlorobenzyl)amino)-2-((3,4-difluorophenyl)ethynyl)-9H-purin-9-yl)-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide；(1S,2R,3S,4R,5S)-4-[6-[[(3-Chlorophenyl)methyl]amino]-2-[2-(3,4-difluorophenyl)ethynyl]-9H-purin-9-yl]-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide；(1S,2R,3S,4R,5S)-4-[6-[(3-chlorophenyl)methylamino]-2-[2-(3,4-difluorophenyl)ethynyl]purin-9-yl]-2,3-dihydroxy-N-methylbicyclo[3.1.0]hexane-1-carboxamide
• CAS: 1377273-00-1
• 化学式: C₂₈H₂₃ClF₂N₆O₃
• 分子量: 564.979
• InChiKey: LYLLLJJYBWLGHW-CIZVZKTGSA-N

物化性质

• 密度：
  1.58±0.1 g/cm3(Predicted)
• 溶解度：
  溶于二甲基亚砜

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  40
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  125
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  N-Boc-L-缬氨酸 、 (1S，2R，3S，4R，5S)-4-[6-[[((3-氯苯基)甲基]氨基]-2-[2-(3,4-二氟苯基)乙炔基]-9H-嘌呤-9-yl]-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-羧酰胺 在 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 、 三甲胺 作用下， 以 二氯甲烷 为溶剂， 反应 18.5h， 以250 mg的产率得到
  参考文献：
  名称：

  [EN] COMPOUNDS AND METHODS FOR MODULATION OF G-PROTEIN-COUPLED RECEPTORS
  [FR] COMPOSÉS ET PROCÉDÉS DE MODULATION DE RÉCEPTEURS COUPLÉS À LA PROTÉINE G

  摘要：

  公开号：

  WO2019232554A3
• 作为产物：
  描述：

  (1'S,2'R,3'S,4'S,5'S)-4'-[6-(3-chlorobenzylamino)-2-iodopurin-9-yl]-2',3'-O-isopropylidenebicyclo[3.1.0]hexane-1'-carboxylic acid N-methylamine 在 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.0h， 生成 (1S，2R，3S，4R，5S)-4-[6-[[((3-氯苯基)甲基]氨基]-2-[2-(3,4-二氟苯基)乙炔基]-9H-嘌呤-9-yl]-2,3-二羟基-N-甲基双环[3.1.0]己烷-1-羧酰胺
  参考文献：
  名称：

  Structure-Guided Design of A₃ Adenosine Receptor-Selective Nucleosides: Combination of 2-Arylethynyl and Bicyclo[3.1.0]hexane Substitutions

  摘要：

  (N)-Methanocarba adenosine 5'-methyluronamides containing known A(3) AR (adenosine receptor)enhancing modifications, i.e., 2-(arylethynyl)adenine and N-6-methyl or N-6-(3-substituted-benzyl), were nanomolar full agonists of human (h) A(3)AR and highly selective (K-i similar to 0.6 nM, N-6-methyl 2-(halophenylethynyl) analogues 13 and 14). Combined 2-arylethynyl-N-6-3-chlorobenzyl substitutions preserved A(3)AR affinity/selectivity in the (N)-methanocarba series (e.g., 3,4-difluoro full agonist MRS5698 31, K-i 3 nM, human and mouse A(3)) better than that for ribosides. Polyaromatic 2-ethynyl N-6-3-chlorobenzyl analogues, such as potent linearly extended 2-p-biphenylethynyl MRS5679 34 (K-i hA(3) 3.1 nM; A(1), A(2A), inactive) and fluorescent 1-pyrene adduct MRS5704 35 (K-i hA(3) 68.3 nM), were conformationally rigid; receptor docking identified a large, mainly hydrophobic binding region. The vicinity of receptor-bound C2 groups was probed by homology modeling based on recent X-ray structure of an agonist-bound A(2A)AR, with a predicted helical rearrangement requiring an agonist-specific outward displacement of TM2 resembling opsin. Thus, the X-ray structure of related A(2A)AR is useful in guiding the design of new A(3)AR. agonists.

  DOI：

  10.1021/jm300396n

文献信息

• Design and in vivo activity of A3 adenosine receptor agonist prodrugs
  作者：R. Rama Suresh、Shanu Jain、Zhoumou Chen、Dilip K. Tosh、Yanling Ma、Maren C. Podszun、Yaron Rotman、Daniela Salvemini、Kenneth A. Jacobson

  DOI：10.1007/s11302-020-09715-0

  日期：2020.9

  normalized in the MRS7476-treated mice, but not liver fibrosis (no change in ACTA2 levels) or inflammation. Hepatic expression of ADORA3 in human NAFLD patients was 1.9-fold lower compared to normal controls. Adora3 expression determined by qPCR in primary mouse liver was associated with the stellate cells, and its mouse full body A3AR knockout worsened liver markers of inflammation and steatosis. Thus, we

  高选择性 A 3腺苷受体 (AR) 激动剂 Cl-IB-MECA 和 MRS5698 的前药（MRS7422、MRS7476）分别通过 2' 和 3' 羟基的琥珀酰化合成，母体活性药物显示与肝酯酶一起孵育后很容易释放。与母体 MRS5698 相比，前药 MRS7476 的水溶性大大增加，并且在逆转小鼠神经性疼痛（慢性缩窄性损伤模型，3 μmol/kg，po）（一种已知的 A 3 AR 效应）方面完全有效且持续时间比 MRS7422 更长。在 STAM 小鼠模型中，发现 MRS7476（5 毫克/千克，口服，每日两次）可预防非酒精性脂肪性肝炎 (NASH)，NAFLD 活动评分表明。在 MRS7476 治疗的小鼠中，肝细胞膨胀、IL-10 产生和肝脏组织学显着正常化，但肝纤维化（ACTA2 水平没有变化）或炎症没有正常化。人类 NAFLD 患者的ADORA3肝脏表达比正常对照低 1.9 倍。通过
• Compounds and methods for treating neurological and cardiovascular conditions
  申请人：Astrocyte Pharmaceuticals, Inc.

  公开号：US10265338B2

  公开（公告）日：2019-04-23

  The present invention relates to compounds and methods of use thereof for treatment of certain disorders and conditions, for example brain injuries such as stroke or traumatic brain injuries.

  本发明涉及用于治疗某些疾病和病症（例如脑损伤，如中风或脑外伤）的化合物及其使用方法。
• Optical control of adenosine A3 receptor function in psoriasis
  作者：Marc López-Cano、Ingrid Filgaira、Ernest G. Nolen、Gisela Cabré、Jordi Hernando、Dilip K. Tosh、Kenneth A. Jacobson、Concepció Soler、Francisco Ciruela

  DOI：10.1016/j.phrs.2021.105731

  日期：2021.8
• A3 ADENOSINE RECEPTOR AGONISTS AND ANTAGONISTS
  申请人：Jacobson Kenneth A.

  公开号：US20120184569A1

  公开（公告）日：2012-07-19

  Disclosed are (N)-methanocarba adenine nucleosides of formulas (I)-(V), for example, of formula (V): as highly potent A 3 adenosine receptor agonists, pharmaceutical compositions comprising such nucleosides, and a method of use of these nucleosides, wherein R 1 -R 6 are as defined in the specification. These nucleosides exhibit similar selectivities as agonists of the A 3 versus the A 1 receptor for both human and mouse adenosine receptors, and are contemplated for use in the treatment a number of diseases, for example, inflammation, cardiac ischemia, stroke, asthma, diabetes, and cardiac arrhythmias.
• COMPOUNDS AND METHODS FOR TREATING NEUROLOGICAL AND CARDIOVASCULAR CONDITIONS
  申请人：Astrocyte Pharmaceuticals, Inc.

  公开号：US20180021363A1

  公开（公告）日：2018-01-25

  The present invention relates to compounds and methods of use thereof for treatment of certain disorders and conditions, for example brain injuries such as stroke or traumatic brain injuries.