(S)-3-(3-thiophen-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester | 915233-44-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (S)-3-(3-thiophen-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl (3S)-3-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate
• CAS: 915233-44-2
• 化学式: C₁₆H₂₁N₃O₃S
• 分子量: 335.427
• InChiKey: IPYBVUCPQDENIQ-NSHDSACASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  96.7
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (S)-3-(3-thiophen-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester 在 盐酸 、 1-羟基苯并三唑 、 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 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.08h， 生成 4,4,4-trifluoro-1-[(S)-3-(3-thiophen-2-yl-1,2,4-oxadiazol-5-yl)-piperidin1-yl]-butan-1-one
  参考文献：
  名称：

  Ethionamide Boosters: Synthesis, Biological Activity, and Structure−Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors

  摘要：

  We report in this article an extensive structure activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were 6:Insistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.

  DOI：

  10.1021/jm200076a
• 作为产物：
  描述：

  2-氰基噻吩 在 盐酸羟胺 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.08h， 生成 (S)-3-(3-thiophen-2-yl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Ethionamide Boosters: Synthesis, Biological Activity, and Structure−Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors

  摘要：

  We report in this article an extensive structure activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were 6:Insistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.

  DOI：

  10.1021/jm200076a

文献信息

• Novel Oxadiazole Derivatives and Their Use as Positive Allosteric Modulators of Metabotropic Glutamate Receptors
  申请人：Bugada Piergiuliano

  公开号：US20090197897A1

  公开（公告）日：2009-08-06

  The present invention relates to new compounds which are Oxadiazole derivatives of formula (I) wherein B, P, Q, W, R 1 and R 2 are defined in the description. Invention compounds are useful in the prevention or treatment of central or peripheral nervous system disorders as well as other disorders modulated by mGluR5 receptors.

  本发明涉及一种新的化合物，其为公式(I)的Oxadiazole衍生物，其中B、P、Q、W、R1和R2在说明中定义。本发明化合物在预防或治疗中枢或外周神经系统疾病以及其他受mGluR5受体调节的疾病中有用。
• NOVEL OXADIAZOLE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS
  申请人：ADDEX Pharma S.A.

  公开号：EP1896463A2

  公开（公告）日：2008-03-12
• [EN] NOVEL OXADIAZOLE DERIVATIVES AND THEIR USE AS POSITIVE ALLOSTERIC MODULATORS OF METABOTROPIC GLUTAMATE RECEPTORS<br/>[FR] NOUVEAUX DERIVES D'OXADIAZOLE ET LEUR UTILISATION COMME MODULATEURS ALLOSTERIQUES POSITIFS DES RECEPTEURS METABOTROPIQUES DU GLUTAMATE
  申请人：ADDEX PHARMACEUTICALS SA

  公开号：WO2006123249A2

  公开（公告）日：2006-11-23

  [EN] The present invention relates to new compounds which are Oxadiazole derivatives of formula (I) wherein B, P, Q,W, R₁ and R₂ are defined in the description. Invention compounds are useful in the prevention or treatment of central or peripheral nervous system disorders as well as other disorders modulated by mGluR5 receptors.
  [FR] La présente invention concerne de nouveaux composés qui sont des dérivés d'oxadiazole représentés par la formule générale (I). Dans cette formule, B, P, Q, W, R₁ et R₂ désignent des éléments définis dans la description. Ces composés sont utiles pour le traitement ou la prévention de troubles du système nerveux central ou périphérique ainsi que d'autres troubles modulés par les récepteurs mGluR5.
• Ethionamide Boosters: Synthesis, Biological Activity, and Structure−Activity Relationships of a Series of 1,2,4-Oxadiazole EthR Inhibitors
  作者：Marion Flipo、Matthieu Desroses、Nathalie Lecat-Guillet、Bertrand Dirié、Xavier Carette、Florence Leroux、Catherine Piveteau、Fatma Demirkaya、Zoé Lens、Prakash Rucktooa、Vincent Villeret、Thierry Christophe、Hee Kyoung Jeon、Camille Locht、Priscille Brodin、Benoit Déprez、Alain R. Baulard、Nicolas Willand

  DOI：10.1021/jm200076a

  日期：2011.4.28

  We report in this article an extensive structure activity relationships (SAR) study with 58 thiophen-2-yl-1,2,4-oxadiazoles as inhibitors of EthR, a transcriptional regulator controling ethionamide bioactivation in Mycobacterium tuberculosis. We explored the replacement of two key fragments of the starting lead BDM31343. We investigated the potency of all analogues to boost subactive doses of ethionamide on a phenotypic assay involving M. tuberculosis infected macrophages and then ascertained the mode of action of the most active compounds using a functional target-based surface plasmon resonance assay. This process revealed that introduction of 4,4,4-trifluorobutyryl chain instead of cyanoacetyl group was crucial for intracellular activity. Replacement of 1,4-piperidyl by (R)-1,3-pyrrolidyl scaffold did not enhance activity but led to improved pharmacokinetic properties. Furthermore, the crystal structures of ligand-EthR complexes were 6:Insistent with the observed SAR. In conclusion, we identified EthR inhibitors that boost antibacterial activity of ethionamide with nanomolar potency while improving solubility and metabolic stability.