4,4,4-trifluoro-1-[4-(3-p-tolyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]butan-1-one | 1352079-12-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4,4,4-trifluoro-1-[4-(3-p-tolyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]butan-1-one
• 英文别名: 4,4,4-Trifluoro-1-[4-[3-(p-tolyl)-1,2,4-oxadiazol-5-yl]-1-piperidyl]butan-1-one；4,4,4-trifluoro-1-[4-[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]piperidin-1-yl]butan-1-one
• CAS: 1352079-12-9
• 化学式: C₁₈H₂₀F₃N₃O₂
• 分子量: 367.371
• InChiKey: MFDDHUFVSSLLCL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  59.2
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-[3-(4-methylphenyl)[1,2,4]oxadiazol-5-yl]piperidine hydrochloride 、 4,4,4-三氟丁酸 在 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 N,N-二甲基甲酰胺 为溶剂， 反应 0.08h， 以75%的产率得到4,4,4-trifluoro-1-[4-(3-p-tolyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl]butan-1-one
  参考文献：
  名称：

  Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors

  摘要：

  Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, a second phase of optimization was required. Herein a structure-property relationship study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.

  DOI：

  10.1021/jm200825u

文献信息

• Ethionamide Boosters. 2. Combining Bioisosteric Replacement and Structure-Based Drug Design To Solve Pharmacokinetic Issues in a Series of Potent 1,2,4-Oxadiazole EthR Inhibitors
  作者：Marion Flipo、Matthieu Desroses、Nathalie Lecat-Guillet、Baptiste Villemagne、Nicolas Blondiaux、Florence Leroux、Catherine Piveteau、Vanessa Mathys、Marie-Pierre Flament、Juergen Siepmann、Vincent Villeret、Alexandre Wohlkönig、René Wintjens、Sameh H. Soror、Thierry Christophe、Hee Kyoung Jeon、Camille Locht、Priscille Brodin、Benoit Déprez、Alain R. Baulard、Nicolas Willand

  DOI：10.1021/jm200825u

  日期：2012.1.12

  Mycobacterial transcriptional repressor EthR controls the expression of EthA, the bacterial monooxygenase activating ethionamide, and is thus largely responsible for the low sensitivity of the human pathogen Mycobacterium tuberculosis to this antibiotic. We recently reported structure-activity relationships of a series of 1,2,4-oxadiazole EthR inhibitors leading to the discovery of potent ethionamide boosters. Despite high metabolic stability, pharmacokinetic evaluation revealed poor mice exposure; therefore, a second phase of optimization was required. Herein a structure-property relationship study is reported according to the replacement of the two aromatic heterocycles: 2-thienyl and 1,2,4-oxadiazolyl moieties. This work was done using a combination of structure-based drug design and in vitro/ex vivo evaluations of ethionamide boosters on the targeted protein EthR and on the human pathogen Mycobacterium tuberculosis. Thanks to this process, we identified compound 42 (BDM41906), which displays improved efficacy in addition to high exposure to mice after oral administration.