6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-amine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩并吡啶类
• 英文名称: 6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-amine
• 英文别名: 6-ethyl-3-(1,3,4-oxadiazol-2-yl)-5,7-dihydro-4H-thieno[2,3-c]pyridin-2-amine
• 化学式: C₁₁H₁₄N₄OS
• 分子量: 250.324
• InChiKey: BHRNORYUYFILDG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  17
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 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：

  6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-amine 、 对氯苯异氰酸酯 在 sodium hydride 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 0.83h， 以82%的产率得到1-(4-chlorophenyl)-3-[6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-yl]urea
  参考文献：
  名称：

  Phenotypic Optimization of Urea–Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss

  摘要：

  Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a ureathiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 mu M with protection against 200 mu M neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structureactivity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.

  DOI：

  10.1021/acs.jmedchem.7b00932
• 作为产物：
  描述：

  2-氨基-6-乙基-4,5,6,7-四氢噻吩并[2,3-C]吡啶-3-羧酸乙酯 在 4-二甲氨基吡啶 、 盐酸肼 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 53.0h， 生成 6-ethyl-3-(1,3,4-oxadiazol-2-yl)-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-2-amine
  参考文献：
  名称：

  Phenotypic Optimization of Urea–Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss

  摘要：

  Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a ureathiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 mu M with protection against 200 mu M neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structureactivity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.

  DOI：

  10.1021/acs.jmedchem.7b00932

文献信息

• COMPOUNDS AND METHODS FOR PREVENTING, TREATING AND/OR PROTECTING AGAINST SENSORY HAIR CELL DEATH
  申请人：UNIVERSITY OF WASHINGTON THROUGH ITS CENTER FOR COMMERCIALIZATION

  公开号：US20150232476A1

  公开（公告）日：2015-08-20

  Disclosed herein are compounds, and pharmaceutical compositions that include such compounds, for preventing, treating, and/or protecting against sensory hair cell death. Methods of using the compounds, alone or in combination with other therapeutic agents, are also disclosed.

  本文披露了一些化合物和包含这些化合物的药物组成物，用于预防、治疗和/或保护感觉毛细胞死亡。还披露了使用这些化合物的方法，单独或与其他治疗剂联合使用。
• US9416141B2
  申请人：——

  公开号：US9416141B2

  公开（公告）日：2016-08-16
• US9902738B2
  申请人：——

  公开号：US9902738B2

  公开（公告）日：2018-02-27
• Phenotypic Optimization of Urea–Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss
  作者：Sarwat Chowdhury、Kelly N. Owens、R. Jason Herr、Qin Jiang、Xinchao Chen、Graham Johnson、Vincent E. Groppi、David W. Raible、Edwin W Rubel、Julian A. Simon

  DOI：10.1021/acs.jmedchem.7b00932

  日期：2018.1.11

  Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a ureathiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 mu M with protection against 200 mu M neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structureactivity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.