(R)-2-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetic acid | 1007878-10-5

• 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: (R)-2-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetic acid
• 英文别名: 2(R)-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetic acid；(2R)-2-[(3S)-3-fluoropyrrolidin-1-yl]-2-phenylacetic acid
• CAS: 1007878-10-5
• 化学式: C₁₂H₁₄FNO₂
• 分子量: 223.247
• InChiKey: ZLAKPURGNBLUCC-WDEREUQCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 达卡他韦中间体 、 (R)-2-((S)-3-fluoropyrrolidin-1-yl)-2-phenylacetic 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 N,N-二甲基甲酰胺 、 甲醇 、 水 为溶剂， 生成 2-[(3S)-3-fluoropyrrolidin-1-yl]-1-[(2S)-2-{5-[4-(4-{2-[(2S)-1-{2-[(3S)-3-fluoropyrrolidin-1-yl]-2-phenylacetyl}pyrrolidin-2-yl]-1H-imidazol-5-yl}phenyl)phenyl]-1H-imidazol-2-yl}pyrrolidin-1-yl]-2-phenylethan-1-one trifluoroacetic acid
  参考文献：
  名称：

  Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir

  摘要：

  The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure- activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.

  DOI：

  10.1021/jm401836p

文献信息

• Hepatitis C Virus Inhibitors
  申请人：Lavoie Rico

  公开号：US20110281910A1

  公开（公告）日：2011-11-17

  This disclosure concerns novel compounds of Formula (I) or as defined in the specification and compositions comprising such novel compounds. These compounds are useful antiviral agents, especially in inhibiting the function of the NS5A protein encoded by Hepatitis C virus (HCV). Thus, the disclosure also concerns a method of treating HCV related diseases or conditions by use of these novel compounds or a composition comprising such novel compounds.

  本公开涉及公式（I）的新化合物或如规范中定义的化合物和包含这些新化合物的组合物。这些化合物是有用的抗病毒剂，特别是在抑制由丙型肝炎病毒（HCV）编码的NS5A蛋白的功能方面。因此，本公开还涉及使用这些新化合物或包含这些新化合物的组合物治疗HCV相关疾病或病状的方法。
• Hepatitis C Virus NS5A Replication Complex Inhibitors: The Discovery of Daclatasvir
  作者：Makonen Belema、Van N. Nguyen、Carol Bachand、Dan H. Deon、Jason T. Goodrich、Clint A. James、Rico Lavoie、Omar D. Lopez、Alain Martel、Jeffrey L. Romine、Edward H. Ruediger、Lawrence B. Snyder、Denis R. St. Laurent、Fukang Yang、Juliang Zhu、Henry S. Wong、David R. Langley、Stephen P. Adams、Glenn H. Cantor、Anjaneya Chimalakonda、Aberra Fura、Benjamin M. Johnson、Jay O. Knipe、Dawn D. Parker、Kenneth S. Santone、Robert A. Fridell、Julie A. Lemm、Donald R. O’Boyle、Richard J. Colonno、Min Gao、Nicholas A. Meanwell、Lawrence G. Hamann

  DOI：10.1021/jm401836p

  日期：2014.3.13

  The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure- activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.