2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide | 1400647-71-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide
• 英文别名: 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-3,4-dihydro-1H-isoquinoline-6-sulfonamide
• CAS: 1400647-71-3
• 化学式: C₂₇H₃₁FN₂O₂S
• 分子量: 466.62
• InChiKey: XTJMRCLOINUNKE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  57.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 反应 3.0h， 以115 mg的产率得到2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide monohydrochloride
  参考文献：
  名称：

  Identification of 2-[2-(4-<i>tert</i>-Butylphenyl)ethyl]-<i>N</i>-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor

  摘要：

  我们之前报道了2-[2-(4-叔丁基苯基)乙基]-N-(4-氟苯基)-1,2,3,4-四氢异喹啉-6-磺酰胺2，这是一种口服可用的单酰甘油酰基转移酶2（MGAT2）抑制剂，在小鼠口服脂质耐受测试中以100 mg/kg的剂量表现出体内疗效。对化合物2进行进一步优化以提高内在效力，最终确定了化合物11。化合物11对人类MGAT2酶的IC50值比2低超过50倍。在口服脂质耐受测试中以3 mg/kg的剂量口服给药11导致三酸甘油脂合成显著抑制。

  DOI：

  10.1248/cpb.c15-00803
• 作为产物：
  描述：

  1-(3,4-二氢-2(1H)-异喹啉基)-2,2,2-三氟乙烷酮 在 吡啶 、 氯磺酸 、 4-二甲氨基吡啶 、 硼烷四氢呋喃络合物 、 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 氯仿 为溶剂， 反应 56.0h， 生成 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide
  参考文献：
  名称：

  Identification of 2-[2-(4- tert -butylphenyl)ethyl]- N -(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide ( 29 ) as an orally available MGAT2 inhibitor

  摘要：

  MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity relationship (SAR) study of 2,3-dihydro-1H-isoindole-5-sulfonamide derivatives. In this study, we identified 29 as an orally available inhibitor of MGAT2 through optimization especially in terms of solubility. This compound exhibited moderate potency in the enzyme inhibitory assay (IC50 = 1522 nM) and significant suppression of fat absorption (57% inhibition) in mice oral lipid tolerance test. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.06.065

文献信息

• NITROGEN-CONTAINING CONDENSED HETEROCYCLIC COMPOUND
  申请人：Taisho Pharmaceutical Co., Ltd.

  公开号：EP2687507B1

  公开（公告）日：2016-03-09
• US9035059B2
  申请人：——

  公开号：US9035059B2

  公开（公告）日：2015-05-19
• Identification of 2-[2-(4-&lt;i&gt;tert&lt;/i&gt;-Butylphenyl)ethyl]-&lt;i&gt;N&lt;/i&gt;-[4-(3-cyclopentylpropyl)-2-fluorophenyl]-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide as an Orally Active MGAT2 Inhibitor
  作者：Tsuyoshi Busujima、Hiroaki Tanaka、Kanako Iwakiri、Yoshihisa Shirasaki、Eiji Munetomo、Masako Saito、Aiko Masuko、Kiyokazu Kitano、Fusayo Io、Koji Kato、Shunsuke Kamigaso、Akiko Nozoe、Nagaaki Sato

  DOI：10.1248/cpb.c15-00803

  日期：——

  We previously reported 2-[2-(4-tert-butylphenyl)ethyl]-N-(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide 2 as on orally available monoacylglycerol acyltransferase 2 (MGAT2) inhibitor which exhibited an in vivo efficacy at an oral dose of 100 mg/kg in a mouse oral lipid tolerance test. Further optimization of compound 2 to improve the intrinsic potency culminated in the identification of compound 11. Compound 11 showed a >50-fold lower IC50 against human MGAT2 enzyme than 2. Oral administration of 11 at a dose of 3 mg/kg in the oral lipid tolerance test resulted in significant suppression of triglyceride synthesis.

  我们之前报道了2-[2-(4-叔丁基苯基)乙基]-N-(4-氟苯基)-1,2,3,4-四氢异喹啉-6-磺酰胺2，这是一种口服可用的单酰甘油酰基转移酶2（MGAT2）抑制剂，在小鼠口服脂质耐受测试中以100 mg/kg的剂量表现出体内疗效。对化合物2进行进一步优化以提高内在效力，最终确定了化合物11。化合物11对人类MGAT2酶的IC50值比2低超过50倍。在口服脂质耐受测试中以3 mg/kg的剂量口服给药11导致三酸甘油脂合成显著抑制。
• Identification of 2-[2-(4- tert -butylphenyl)ethyl]- N -(4-fluorophenyl)-1,2,3,4-tetrahydroisoquinoline-6-sulfonamide ( 29 ) as an orally available MGAT2 inhibitor
  作者：Tsuyoshi Busujima、Hiroaki Tanaka、Yoshihisa Shirasaki、Eiji Munetomo、Masako Saito、Kiyokazu Kitano、Toshiya Minagawa、Koji Yoshida、Naoto Osaki、Nagaaki Sato

  DOI：10.1016/j.bmc.2015.06.065

  日期：2015.9

  MGAT2 (monoacylglycerol acyltransferase 2) is expected to be an attractive target for the drug treatment of obesity, diabetes, and other disease. We describe our exploration and structure-activity relationship (SAR) study of 2,3-dihydro-1H-isoindole-5-sulfonamide derivatives. In this study, we identified 29 as an orally available inhibitor of MGAT2 through optimization especially in terms of solubility. This compound exhibited moderate potency in the enzyme inhibitory assay (IC50 = 1522 nM) and significant suppression of fat absorption (57% inhibition) in mice oral lipid tolerance test. (C) 2015 Elsevier Ltd. All rights reserved.