ethyl (3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline-1-carboxylate

• 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: ethyl (3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline-1-carboxylate
• 英文别名: Ethyl (3R)-3-(4-(5-Fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-beta-carboline-1-carboxylate；ethyl (3R)-1-(1-ethylpyrazol-4-yl)-3-[5-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl]-2,3,4,9-tetrahydropyrido[3,4-b]indole-1-carboxylate
• 化学式: C₂₇H₂₆FN₇O₂
• 分子量: 499.548
• InChiKey: AKPORYSWLIVYJX-XVPAFAEQSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  37
• 可旋转键数：
  7
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  114
• 氢给体数：
  3
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  ethyl (3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline-1-carboxylate 在 potassium carbonate 、 肼 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 1.58h， 生成 (3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline
  参考文献：
  名称：

  Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

  摘要：

  The imidazolyl-tetrahydro-beta-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline (17e, MK-1421).

  DOI：

  10.1021/ml500514w
• 作为产物：
  描述：

  1-乙基-吡唑 在 sodium acetate 作用下， 以 乙醇 为溶剂， 反应 48.0h， 生成 ethyl (3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-2,3,4,9-tetrahydro-1H-β-carboline-1-carboxylate
  参考文献：
  名称：

  Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes

  摘要：

  The imidazolyl-tetrahydro-beta-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline (17e, MK-1421).

  DOI：

  10.1021/ml500514w

文献信息

• OXADIAZOLE BETA CARBOLINE DERIVATIVES AS ANTIDIABETIC COMPOUNDS
  申请人：DU WU

  公开号：US20100184799A1

  公开（公告）日：2010-07-22

  Beta-carboline derivatives of structural formula I are selective antagonists of the somatostatin subtype receptor 3 (SSTR3) and are useful for the treatment of Type 2 diabetes mellitus and of conditions that are often associated with this disease, including hyperglycemia, insulin resistance, obesity, lipid disorders, and hypertension. The compounds are also useful for the treatment of depression and anxiety.

  结构式I的β-咔啉衍生物是生长抑素亚型受体3（SSTR3）的选择性拮抗剂，可用于治疗2型糖尿病以及通常与该疾病相关的病症，包括高血糖、胰岛素抵抗、肥胖、血脂异常和高血压。这些化合物还可用于治疗抑郁症和焦虑症。
• Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes
  作者：Shrenik K. Shah、Shuwen He、Liangqin Guo、Quang Truong、Hongbo Qi、Wu Du、Zhong Lai、Jian Liu、Tianying Jian、Qingmei Hong、Peter Dobbelaar、Zhixiong Ye、Edward Sherer、Zhe Feng、Yang Yu、Frederick Wong、Koppara Samuel、Maria Madiera、Bindhu V. Karanam、Vijay B. Reddy、Stan Mitelman、Sharon X. Tong、Gary G. Chicchi、Kwei-Lan Tsao、Dorina Trusca、Yue Feng、Margaret Wu、Qing Shao、Maria E. Trujillo、George J. Eiermann、Cai Li、Michele Pachanski、Guillermo Fernandez、Donald Nelson、Patricia Bunting、Pierre Morissette、Sylvia Volksdorf、Janet Kerr、Bei B. Zhang、Andrew D. Howard、Yun-Ping Zhou、Alexander Pasternak、Ravi P. Nargund、William K. Hagmann

  DOI：10.1021/ml500514w

  日期：2015.5.14

  The imidazolyl-tetrahydro-beta-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-beta-carboline (17e, MK-1421).