(2S,3S)-2-((R)-2-((tert-butoxycarbonyl)(methyl)amino)-N-methylpropanamido)-4-methoxy-3-methylbutanoic acid

• 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: (2S,3S)-2-((R)-2-((tert-butoxycarbonyl)(methyl)amino)-N-methylpropanamido)-4-methoxy-3-methylbutanoic acid
• 英文别名: (2S,3S)-4-methoxy-3-methyl-2-[methyl-[(2R)-2-[methyl-[(2-methylpropan-2-yl)oxycarbonyl]amino]propanoyl]amino]butanoic acid
• 化学式: C₁₆H₃₀N₂O₆
• 分子量: 346.424
• InChiKey: XKOPUDYLAZDEAS-UTUOFQBUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  24
• 可旋转键数：
  9
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  96.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S,3S)-2-((R)-2-((tert-butoxycarbonyl)(methyl)amino)-N-methylpropanamido)-4-methoxy-3-methylbutanoic acid 、 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 二氯甲烷 为溶剂， 反应 16.0h， 以100%的产率得到
  参考文献：
  名称：

  Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition

  摘要：

  Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

  DOI：

  10.1021/jm500862r
• 作为产物：
  描述：

  (R)-1-(((1S,2S)-1-furan-2-yl-3-methoxypropyl)(methylcarbamoyl)ethyl)methyl carbamic acid tert-butyl ester 在 ruthenium trichloride 、 sodium periodate 作用下， 以 四氯化碳 、 水 、 乙腈 为溶剂， 反应 0.08h， 以88%的产率得到(2S,3S)-2-((R)-2-((tert-butoxycarbonyl)(methyl)amino)-N-methylpropanamido)-4-methoxy-3-methylbutanoic acid
  参考文献：
  名称：

  Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition

  摘要：

  Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.

  DOI：

  10.1021/jm500862r

文献信息

• CYCLIC PEPTIDES AND USE AS MEDICINES
  申请人：Fu Jiping

  公开号：US20140134132A1

  公开（公告）日：2014-05-15

  The present invention provides a compound of formula I; or a pharmaceutically acceptable salt thereof, wherein the variables R 1 , R 2 , R 3 , R 4 , R 5 , and A-B are defined herein, which are non-immunosuppresive, cyclophilin-binding, mPTP blockers and are therefore useful for the prevention or treatment of diseases or disorders such as HCV infection, stroke, multiple sclerosis, HBV infection, HPV infection, asthma, cancer, muscular dystrophy, sepsis, ischemia/reperfusion injury, and heart failure.

  本发明提供了一种化合物I的公式；或其药学上可接受的盐，其中变量R1、R2、R3、R4、R5和A-B在此处定义，这些化合物是非免疫抑制剂、环肽酶结合剂、mPTP阻滞剂，因此可用于预防或治疗HCV感染、中风、多发性硬化、HBV感染、HPV感染、哮喘、癌症、肌萎缩症、败血症、缺血/再灌注损伤和心力衰竭等疾病或紊乱。
• US9072696B2
  申请人：——

  公开号：US9072696B2

  公开（公告）日：2015-07-07
• US9566312B2
  申请人：——

  公开号：US9566312B2

  公开（公告）日：2017-02-14
• Potent Nonimmunosuppressive Cyclophilin Inhibitors With Improved Pharmaceutical Properties and Decreased Transporter Inhibition
  作者：Jiping Fu、Meiliana Tjandra、Christopher Becker、Dallas Bednarczyk、Michael Capparelli、Robert Elling、Imad Hanna、Roger Fujimoto、Markus Furegati、Subramanian Karur、Theresa Kasprzyk、Mark Knapp、Kwan Leung、Xiaolin Li、Peichao Lu、Wosenu Mergo、Charlotte Miault、Simon Ng、David Parker、Yunshan Peng、Silvio Roggo、Alexey Rivkin、Robert L. Simmons、Michael Wang、Brigitte Wiedmann、Andrew H. Weiss、Linda Xiao、Lili Xie、Wenjian Xu、Aregahegn Yifru、Shengtian Yang、Bo Zhou、Zachary K. Sweeney

  DOI：10.1021/jm500862r

  日期：2014.10.23

  Nonimmunosuppressive cyclophilin inhibitors have demonstrated efficacy for the treatment of hepatitis C infection (HCV). However, alisporivir, cyclosporin A, and most other cyclosporins are potent inhibitors of OATP1B1, MRP2, MDR1, and other important drug transporters. Reduction of the side chain hydrophobicity of the P4 residue preserves cyclophilin binding and antiviral potency while decreasing transporter inhibition. Representative inhibitor 33 (NIM258) is a less potent transporter inhibitor relative to previously described cyclosporins, retains anti-HCV activity in cell culture, and has an acceptable pharmacokinetic profile in rats and dogs. An X-ray structure of 33 bound to rat cyclophilin D is reported.