N-(4,5-dimethyl-1,3-thiazol-2-yl)-9H-xanthene-9-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: N-(4,5-dimethyl-1,3-thiazol-2-yl)-9H-xanthene-9-carboxamide
• 化学式: C₁₉H₁₆N₂O₂S
• 分子量: 336.414
• InChiKey: MALULYIDGNXSNH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.16
• 拓扑面积：
  79.5
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氨基-4,5-二甲基噻唑 、 呫吨-9-甲酸 在 N,N-二异丙基乙胺 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 生成 N-(4,5-dimethyl-1,3-thiazol-2-yl)-9H-xanthene-9-carboxamide
  参考文献：
  名称：

  Re-exploration of the mGlu1 PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR

  摘要：

  This letter describes the re-exploration of the mGlu(1) PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu(1) PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only similar to 6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu(5) PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and similar to 3- to 4-fold improvement in CNS exposure (K(p)s 1.01-1.19); albeit, with a similar to 3-fold diminution in mGlu1 PAM potency, yet comparable efficacy (similar to 5-fold leftward shift of the glutamate concentration-response curve at 10 mu M). Thus, this effort has provided additional CNS penetrant mGlu(1) PAM tools in a different chemotype than the VU0486321 scaffold. These compounds will permit a better understanding of the pharmacology and therapeutic potential of selective mGlu(1) activation, while highlighting the steep SAR challenges that can often be encountered in GPCR allosteric modulator discovery. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.03.044

文献信息

• Re-exploration of the mGlu1 PAM Ro 07-11401 scaffold: Discovery of analogs with improved CNS penetration despite steep SAR
  作者：Pedro M. Garcia-Barrantes、Hyekyung P. Cho、Tahj M. Starr、Anna L. Blobaum、Colleen M. Niswender、P. Jeffrey Conn、Craig W. Lindsley

  DOI：10.1016/j.bmcl.2016.03.044

  日期：2016.5

  This letter describes the re-exploration of the mGlu(1) PAM Ro 07-11401 scaffold through a multi-dimensional, iterative parallel synthesis approach. Unlike recent series of mGlu(1) PAMs with robust SAR, the SAR around the Ro 07-11401 structure was incredibly steep (only similar to 6 of 200 analogs displayed mGlu1 PAM activity), and reminiscent of the CPPHA mGlu(5) PAM scaffold. Despite the steep SAR, two new thiazole derivatives were discovered with improved in vitro DMPK profiles and similar to 3- to 4-fold improvement in CNS exposure (K(p)s 1.01-1.19); albeit, with a similar to 3-fold diminution in mGlu1 PAM potency, yet comparable efficacy (similar to 5-fold leftward shift of the glutamate concentration-response curve at 10 mu M). Thus, this effort has provided additional CNS penetrant mGlu(1) PAM tools in a different chemotype than the VU0486321 scaffold. These compounds will permit a better understanding of the pharmacology and therapeutic potential of selective mGlu(1) activation, while highlighting the steep SAR challenges that can often be encountered in GPCR allosteric modulator discovery. (C) 2016 Elsevier Ltd. All rights reserved.