2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-2-methyl-propionic acid | 491582-41-3

• 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: 2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-2-methyl-propionic acid
• 英文别名: 2-[[1-Cyclohexyl-2-(furan-3-yl)benzimidazole-5-carbonyl]amino]-2-methylpropanoic acid
• CAS: 491582-41-3
• 化学式: C₂₂H₂₅N₃O₄
• 分子量: 395.458
• InChiKey: FXUNLDVTHUQOTL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  97.4
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-2-methyl-propionic acid 、 (E)-ethyl 3-(4-aminophenyl)acrylate 、 三氟乙酸 在 4-二甲氨基吡啶 、 bromo-tris-dimethylamino-phosphonium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 22.0h， 以57%的产率得到(R,E)-3-(4-(2-(1-cyclohexyl-2-(furan-3-yl)-1H-benzo[d]imidazole-5-carboxamido)propanamido)phenyl)acrylic acid compound with 2,2,2-trifluoroacetic acid (1:1)
  参考文献：
  名称：

  Importance of Ligand Bioactive Conformation in the Discovery of Potent Indole-Diamide Inhibitors of the Hepatitis C Virus NS5B

  摘要：

  Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate "structural hinge" that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.

  DOI：

  10.1021/ja101358s
• 作为产物：
  描述：

  在 sodium hydroxide 、 水 作用下， 以 二甲基亚砜 为溶剂， 反应 4.0h， 生成 2-{[1-(1-cyclohexyl-2-furan-3-yl-1H-benzoimidazol-5-yl)-methanoyl]-amino}-2-methyl-propionic acid
  参考文献：
  名称：

  Viral polymerase inhibitors

  摘要：

  公式I所代表的化合物的异构体、对映体、非对映异构体或互变异构体，其中R1选自：H、卤代烷基、(C1-6)烷基、(C2-6)烯基、(C3-7)环烷基、(C2-6)炔基、(C5-7)环烯基、6或10元芳基、Het均可选择性地取代；R2选自(C1-6)烷基、(C3-7)环烷基、(C6-10)双环烷基、6-或10元芳基、或Het均可选择性地取代；B为N或CR5，其中R5为H、卤素、卤代烷基、(C1-6)烷基、(C3-7)环烷基或(C1-6)烷基-(C3-7)环烷基；X为N或CR5；D为N或CR5；Y1和Y2中的每一个独立地为O或S；Z为O、N或NRz，其中Rz为H、(C1-6)烷基、(C3-7)环烷基或(C1-6)烷基-(C3-7)环烷基；R3和R4各自独立地为H、(C1-6)烷基、第一(C3-7)环烷基或6-或10元芳基、Het(C1-6)烷基-6-或10元芳基、(C1-6)烷基-Het；或每个R3和R4独立地共价结合在一起形成第二(C3-7)环烷基，或杂环，均可选择性地取代；或当Z为N时，R3或R4中的任一者独立地与之共价结合形成含氮杂环；R7为H、(C1-6烷基)、(C3-7)环烷基或(C1-6)烷基-(C3-7)环烷基；或R7与R3或R4中的任一者共价结合形成杂环；A为(C1-6)烷基-CONHR8，其中R8为6-或10元芳基，或Het；或A为6-或10元芳基，或Het所述芳基或Het可选择性地取代；或其盐或衍生物；这类化合物是HCV NS5B聚合酶的有效抑制剂。

  公开号：

  US20030236251A1

文献信息

• VIRAL POLYMERASE INHIBITORS
  申请人：BOEHRINGER INGELHEIM (CANADA) LTD.

  公开号：EP1411928A1

  公开（公告）日：2004-04-28
• US6841566B2
  申请人：——

  公开号：US6841566B2

  公开（公告）日：2005-01-11
• [EN] VIRAL POLYMERASE INHIBITORS<br/>[FR] INHIBITEURS DE POLYMERASE VIRALE
  申请人：BOEHRINGER INGELHEIM CA LTD

  公开号：WO2003007945A1

  公开（公告）日：2003-01-30

  An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula (I): wherein R1 is selected from: H, haloalkyl, (C¿1-6?)alkyl, (C2-6)alkenyl, (C3-7)cycloalkyl, (C2-6)alkynyl, (C5-7)cycloalkenyl, 6 or 10-membered aryl, Het all optionally substituted; R2 is selected from (C1-6)alkyl, (C3-7)cycloalkyl, (C6-10)bicycloalkyl, 6- or 10-membered aryl, or Het all optionally substituted; B is N or CR?5¿, wherein R5 is H, halogen, haloalkyl, (C¿1-6?)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; X is N or CR?5¿; D is N or CR5; each of Y¿1? and Y2 is independently O or S; Z is O, N, or NR?z¿ wherein Rz is H, (C¿1-6?)alkyl, (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; R?3 and R4¿ are each independently H, (C¿1-6?)alkyl, first (C3-7)cycloalkyl, 6- or 10-membered aryl, Het (C1-6)alkyl-6- or 10-membered aryl, (C1-6)alkyl-Het; or each R?3 and R4¿ are independently covalently bonded together to form second (C¿3-7?)cycloalkyl, or heterocycle, all optionally substituted; or when Z is N, either R?3 or R4¿ are independently covalently bonded thereto to form a nitrogen-containing heterocycle; R7 is H, (C¿1-6? alkyl), (C3-7)cycloalkyl or (C1-6)alkyl-(C3-7)cycloalkyl; or R?7¿ is covalently bonded to either of R3 or R4 to form a heterocycle; A is (C¿1-6?) alkyl-CONHR?8¿ wherein R8 is-6- or 10-membered aryl, or Het; or A is a 6- or 10-membered aryl, or Het said aryl or Het being optionally substituted; or a salt or a derivative thereof; such compounds being potent inhibitors of HCV NS5B polymerase.
• Viral polymerase inhibitors
  申请人：Boehringer Ingelheim (Canada) Ltd.

  公开号：US20030236251A1

  公开（公告）日：2003-12-25

  An isomer, enantiomer, diastereoisomer, or tautomer of a compound, represented by formula I: 1 wherein R 1 is selected from: H, haloalkyl, (C 1-6 )alkyl, (C 2-6 )alkenyl, (C 3-7 )cycloalkyl, (C 2-6 )alkynyl, (C 5-7 )cycloalkenyl, 6 or 10-membered aryl, Het all optionally substituted; R 2 is selected from (C 1-6 )alkyl, (C 3-7 )cycloalkyl, (C 6-10 )bicycloalkyl, 6- or 10-membered aryl, or Het all optionally substituted; B is N or CR 5 , wherein R 5 is H, halogen, haloalkyl, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; X is N or CR 5 ; D is N or CR 5 ; each of Y 1 and Y 2 is independently O or S; Z is O, N, or NR z wherein R z is H, (C 1-6 )alkyl, (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; R 3 and R 4 are each independently H, (C 1-6 )alkyl, first (C 3-7 )cycloalkyl or 6- or 10-membered aryl, Het (C 1-6 )alkyl-6- or 10-membered aryl, (C 1-6 )alkyl-Het; or each R 3 and R 4 are independently covalently bonded together to form second (C 3-7 )cycloalkyl, or heterocycle, all optionally substituted; or when Z is N, either R 3 or R 4 are independently covalently bonded thereto to form a nitrogen-containing heterocycle; R 7 is H, (C 1-6 alkyl), (C 3-7 )cycloalkyl or (C 1-6 )alkyl-(C 3-7 )cycloalkyl; or R 7 is covalently bonded to either of R 3 or R 4 to form a heterocycle; A is (C 1-6 ) alkyl-CONHR 8 wherein R 8 is-6- or 10-membered aryl, or Het; or A is a 6- or 10-membered aryl, or Het said aryl or Het being optionally substituted; or a salt or a derivative thereof; such compounds being potent inhibitors of HCV NS5B polymerase.

  公式I所代表的化合物的异构体、对映体、非对映异构体或互变异构体，其中R1选自：H、卤代烷基、(C1-6)烷基、(C2-6)烯基、(C3-7)环烷基、(C2-6)炔基、(C5-7)环烯基、6或10元芳基、Het均可选择性地取代；R2选自(C1-6)烷基、(C3-7)环烷基、(C6-10)双环烷基、6-或10元芳基、或Het均可选择性地取代；B为N或CR5，其中R5为H、卤素、卤代烷基、(C1-6)烷基、(C3-7)环烷基或(C1-6)烷基-(C3-7)环烷基；X为N或CR5；D为N或CR5；Y1和Y2中的每一个独立地为O或S；Z为O、N或NRz，其中Rz为H、(C1-6)烷基、(C3-7)环烷基或(C1-6)烷基-(C3-7)环烷基；R3和R4各自独立地为H、(C1-6)烷基、第一(C3-7)环烷基或6-或10元芳基、Het(C1-6)烷基-6-或10元芳基、(C1-6)烷基-Het；或每个R3和R4独立地共价结合在一起形成第二(C3-7)环烷基，或杂环，均可选择性地取代；或当Z为N时，R3或R4中的任一者独立地与之共价结合形成含氮杂环；R7为H、(C1-6烷基)、(C3-7)环烷基或(C1-6)烷基-(C3-7)环烷基；或R7与R3或R4中的任一者共价结合形成杂环；A为(C1-6)烷基-CONHR8，其中R8为6-或10元芳基，或Het；或A为6-或10元芳基，或Het所述芳基或Het可选择性地取代；或其盐或衍生物；这类化合物是HCV NS5B聚合酶的有效抑制剂。
• Importance of Ligand Bioactive Conformation in the Discovery of Potent Indole-Diamide Inhibitors of the Hepatitis C Virus NS5B
  作者：Steven R. LaPlante、James R. Gillard、Araz Jakalian、Norman Aubry、René Coulombe、Christian Brochu、Youla S. Tsantrizos、Martin Poirier、George Kukolj、Pierre L. Beaulieu

  DOI：10.1021/ja101358s

  日期：2010.11.3

  Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive conformation, and due to its solvent exposure in the complex, reasonable conformation-activity-relationships can be qualitatively attributed. From a ligand design perspective, this feature was exploited by successful linker hopping to an alternate "structural hinge" that led to a new and promising chemical series which matched the ligand bioactive conformation and the pocket bioactive space. Using a combination of X-ray crystallography, NMR and modeling with support from binding-site resistance mutant studies and photoaffinity labeling experiments, we were able to derive inhibitor-polymerase complexes for various chemical series.