2-((1S,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)isonicotinic acid

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 2-((1S,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)isonicotinic acid
• 英文别名: 2-[(1S,3R)-3-[5-(4-fluorophenyl)-1H-imidazol-2-yl]-1-(1-methylpyrazol-4-yl)-2,3,4,9-tetrahydropyrido[3,4-b]indol-1-yl]pyridine-4-carboxylic acid
• 化学式: C₃₀H₂₄FN₇O₂
• 分子量: 533.565
• InChiKey: UHWQSESKOKODEV-AYWVHJORSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.7
• 重原子数：
  40
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.13
• 拓扑面积：
  125
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2-((1S,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)isonicotinic acid 、 三氟乙酸 以 水 、 二甲基亚砜 、 乙腈 为溶剂， 以28 mg的产率得到2-((1S,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)isonicotinic acid trifluoroacetate
  参考文献：
  名称：

  Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

  摘要：

  Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-a-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.

  DOI：

  10.1021/ml500028c
• 作为产物：
  描述：

  2,4-吡啶二羧酸 在 氯化亚砜 、 硅酸四乙酯 、 lithium hydroxide monohydrate 、 水 、 异丙基氯化镁 、 sodium acetate 作用下， 以 四氢呋喃 、 甲醇 、 二甲基亚砜 为溶剂， 反应 54.0h， 生成 2-((1S,3R)-3-(4-(4-fluorophenyl)-1H-imidazol-2-yl)-1-(1-methyl-1H-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)isonicotinic acid
  参考文献：
  名称：

  Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists

  摘要：

  Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-a-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.

  DOI：

  10.1021/ml500028c

文献信息

• Investigation of Cardiovascular Effects of Tetrahydro-β-carboline sstr3 antagonists
  作者：Shuwen He、Zhong Lai、Zhixiong Ye、Peter H. Dobbelaar、Shrenik K. Shah、Quang Truong、Wu Du、Liangqin Guo、Jian Liu、Tianying Jian、Hongbo Qi、Raman K. Bakshi、Qingmei Hong、James Dellureficio、Mikhail Reibarkh、Koppara Samuel、Vijay B. Reddy、Stan Mitelman、Sharon X. Tong、Gary G. Chicchi、Kwei-Lan Tsao、Dorina Trusca、Margaret Wu、Qing Shao、Maria E. Trujillo、Guillermo Fernandez、Donald Nelson、Patricia Bunting、Janet Kerr、Patrick Fitzgerald、Pierre Morissette、Sylvia Volksdorf、George J. Eiermann、Cai Li、Bei Zhang、Andrew D. Howard、Yun-Ping Zhou、Ravi P. Nargund、William K. Hagmann

  DOI：10.1021/ml500028c

  日期：2014.7.10

  Antagonism of somatostatin subtype receptor 3 (sstr3) has emerged as a potential treatment of Type 2 diabetes. Unfortunately, the development of our first preclinical candidate, MK-4256, was discontinued due to a dose-dependent QTc (QT interval corrected for heart rate) prolongation observed in a conscious cardiovascular (CV) dog model. As the fate of the entire program rested on resolving this issue, it was imperative to determine whether the observed QTc prolongation was associated with hERG channel (the protein encoded by the human Ether-a-go-go-Related Gene) binding or was mechanism-based as a result of antagonizing sstr3. We investigated a structural series containing carboxylic acids to reduce the putative hERG off-target activity. A key tool compound, 3A, was identified from this SAR effort. As a potent sstr3 antagonist, 3A was shown to reduce glucose excursion in a mouse oGTT assay. Consistent with its minimal hERG activity from in vitro assays, 3A elicited little to no effect in an anesthetized, vagus-intact CV dog model at high plasma drug levels. These results afforded the critical conclusion that sstr3 antagonism is not responsible for the QTc effects and therefore cleared a path for the program to progress.