(R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid
• 英文别名: (3R)-4-[[4-[5-chloro-2-(6-methoxypyridin-3-yl)phenyl]-1,3-thiazol-2-yl]-cyclopropylamino]-3-(furan-2-ylmethyl)-4-oxobutanoic acid
• 化学式: C₂₇H₂₄ClN₃O₅S
• 分子量: 538.024
• InChiKey: AOZQVWPEWUHYNS-QGZVFWFLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  37
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  134
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  1-(2-溴-5-氯苯基)乙酮 在 2-双环己基膦-2',6'-二甲氧基联苯 、 aluminum (III) chloride 、 tris-(dibenzylideneacetone)dipalladium(0) 、 溴 、 potassium carbonate 、 N,N-二异丙基乙胺 、 三氟乙酸 、 N-[(dimethylamino)-3-oxo-1H-1,2,3-triazolo[4,5-b]pyridin-1-yl-methylene]-N-methylmethanaminium hexafluorophosphate 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 7.0h， 生成 (R)-4-((4-(5-chloro-2-(6-methoxypyridin-3-yl)phenyl)thiazol-2-yl)(cyclopropyl)amino)-3-(furan-2-ylmethyl)-4-oxobutanoic acid
  参考文献：
  名称：

  N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model

  摘要：

  Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp(3)) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (Delta LLE = 0.3, Delta Fsp(3) = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.

  DOI：

  10.1016/j.bmc.2018.09.015

文献信息

• N-Thiazolylamide-based free fatty-acid 2 receptor agonists: Discovery, lead optimization and demonstration of off-target effect in a diabetes model
  作者：Hamid R. Hoveyda、Graeme L. Fraser、Ludivine Zoute、Guillaume Dutheuil、Didier Schils、Cyrille Brantis、Alexey Lapin、Julien Parcq、Sandra Guitard、François Lenoir、Mohamed El Bousmaqui、Sarah Rorive、Sandrine Hospied、Sébastien Blanc、Jérôme Bernard、Frédéric Ooms、Joanne C. McNelis、Jerrold M. Olefsky

  DOI：10.1016/j.bmc.2018.09.015

  日期：2018.10

  Free fatty acid-2 (FFA2) receptor is a G-protein coupled receptor of interest in the development of therapeutics in metabolic and inflammatory disease areas. The discovery and optimization of an N-thiazolylamide carboxylic acid FFA2 agonist scaffold is described. Dual key objectives were to i) evaluate the potential of this scaffold for lead optimization in particular with respect to safety de-risking physicochemical properties, i.e. lipophilicity and aromatic content, and ii) to demonstrate the utility of selected lead analogues from this scaffold in a pertinent in vivo model such as oral glucose tolerance test (OGTT). As such, a concomitant improvement in bioactivity together with lipophilic ligand efficiency (LLE) and fraction sp3 content (Fsp(3)) parameters guided these efforts. Compound 10 was advanced into studies in mice on the basis of its optimized profile vs initial lead 1 (Delta LLE = 0.3, Delta Fsp(3) = 0.24). Although active in OGTT, 10 also displayed similar activity in the FFA2-knockout mice. Given this off-target OGTT effect, we discontinued development of this FFA2 agonist scaffold.