1-[2-(1-cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methyl-propan-1-one tartrate | 1363258-97-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[2-(1-cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methyl-propan-1-one tartrate
• 英文别名: 1-[2-(1-cyclobutylpiperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methylpropan-1-one L-(+)-tartrate
• CAS: 1363258-97-2
• 化学式: C₄H₆O₆*C₁₉H₂₉N₃O₂S
• 分子量: 513.612
• InChiKey: QSKIGGHXASLHQY-LREBCSMRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.96
• 重原子数：
  35.0
• 可旋转键数：
  7.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  160.73
• 氢给体数：
  4.0
• 氢受体数：
  9.0

反应信息

• 作为产物：
  描述：

  N-叔丁氧羰基-4-哌啶酮 在 aluminum (III) chloride 、 亚硝酸特丁酯 、 溴 、 sodium hydride 、 三乙胺 、 三氟乙酸 、 copper(ll) bromide 作用下， 以 四氢呋喃 、 乙醚 、 二氯甲烷 、 异丙醇 、 乙腈 、 mineral oil 为溶剂， 反应 38.5h， 生成 1-[2-(1-cyclobutyl-piperidin-4-yloxy)-6,7-dihydro-4H-thiazolo[5,4-c]pyridin-5-yl]-2-methyl-propan-1-one tartrate
  参考文献：
  名称：

  1‐[2‐(1‐Cyclobutylpiperidin‐4‐yloxy)‐6,7‐dihydro‐4 H ‐thiazolo[5,4‐ c ]pyridin‐5‐yl]propan‐1‐one: a Histamine H ₃ Receptor Inverse Agonist with Efficacy in Animal Models of Cognition

  摘要：

  AbstractA series of chemical optimizations, which was guided by in vitro affinity at histamine H3 receptor (H3R), modulation of lipophilicity, ADME properties and preclinical efficacy resulted in the identification of 1‐[2‐(1‐cyclobutylpiperidin‐4‐yloxy)‐6,7‐dihydro‐4H‐thiazolo[5,4‐c]pyridin‐5‐yl]propan‐1‐one (45 e) as a potent and selective (Ki=4.0 nM) H3R inverse agonist. Dipsogenia induced by (R)‐α‐methylhistamine was dose dependently antagonized by 45 e, confirming its functional antagonism at H3R. It is devoid of hERG and phospholipidosis issues. Compound 45 e has adequate oral exposures and favorable half‐life in both rats and dogs. It has demonstrated high receptor occupancy (ED80=0.22 mg/kg) and robust efficacy in object recognition task and, dose dependently increased acetylcholine levels in brain. The sub‐therapeutic doses of 45 e in combination with donepezil significantly increased acetylcholine levels. The potent affinity, selectivity, in vivo efficacy and drug like properties together with safety, warrant for further development of this molecule for potential treatment of cognitive disorders associated with Alzheimer's disease.

  DOI：

  10.1002/cmdc.202100583