3-(4-{(9H-fluoren-2-ylmethyl)-[4-(4-trifluoromethylphenyl)thiazol-2-yl]amino}benzoylamino)propionic acid | 643012-21-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 芴
• 英文名称: 3-(4-{(9H-fluoren-2-ylmethyl)-[4-(4-trifluoromethylphenyl)thiazol-2-yl]amino}benzoylamino)propionic acid
• 英文别名: Aminothiazole, 25；3-[[4-[9H-fluoren-2-ylmethyl-[4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl]amino]benzoyl]amino]propanoic acid
• CAS: 643012-21-9
• 化学式: C₃₄H₂₆F₃N₃O₃S
• 分子量: 613.66
• InChiKey: GKFODRKFKVOWTH-UHFFFAOYSA-N

物化性质

• 密度：
  1.384±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  7.4
• 重原子数：
  44
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  111
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  Fmoc-β-alanine-loaded 2 chlorotrityl resin 、 2-氟萘烯甲醛 、 2-溴-4'-(三氟甲基)苯乙酮 、 4-硝基苯甲酰氯 、 Fmoc-异硫氰酸 在 哌啶 、 N,N-二异丙基乙胺 作用下， 以 N-甲基吡咯烷酮 为溶剂， 反应 3.5h， 生成 3-(4-{(9H-fluoren-2-ylmethyl)-[4-(4-trifluoromethylphenyl)thiazol-2-yl]amino}benzoylamino)propionic acid
  参考文献：
  名称：

  Human Glucagon Receptor Antagonists with Thiazole Cores. A Novel Series with Superior Pharmacokinetic Properties

  摘要：

  The aim of the work presented here was to design and synthesize potent human glucagon receptor antagonists with improved pharmacokinetic (PK) properties for development of pharmaceuticals for the treatment of type 2 diabetes. We describe the preparation of compounds with cyclic cores (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for rat, mouse, pig, dog, and monkey glucagon receptors. Generally, the compounds had slightly less glucagon receptor affinity compared to compounds of the previous series, but this was compensated for by much improved PK profiles in both rats and dogs with high oral bioavailabilities and sustained high plasma exposures. The compounds generally showed species selectivity for glucagon receptor binding with poor affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One compound of this series, 18, was tested intravenously in an anesthetized glucagon-challenged monkey model of hyperglucagonaemia and hyperglycaemia and was shown dose-dependently to decrease glycaemia. Further, high plasma exposures and a long plasma half-life (5.2 h) were obtained.

  DOI：

  10.1021/jm8016249

文献信息

• Human Glucagon Receptor Antagonists with Thiazole Cores. A Novel Series with Superior Pharmacokinetic Properties
  作者：Peter Madsen、János T. Kodra、Carsten Behrens、Erica Nishimura、Claus B. Jeppesen、Lone Pridal、Birgitte Andersen、Lotte B. Knudsen、Carmen Valcarce-Aspegren、Mette Guldbrandt、Inge T. Christensen、Anker S. Jørgensen、Lars Ynddal、Christian L. Brand、Morten Aa. Bagger、Jesper Lau

  DOI：10.1021/jm8016249

  日期：2009.5.14

  The aim of the work presented here was to design and synthesize potent human glucagon receptor antagonists with improved pharmacokinetic (PK) properties for development of pharmaceuticals for the treatment of type 2 diabetes. We describe the preparation of compounds with cyclic cores (5-aminothiazoles), their binding affinities for the human glucagon and GIP receptors, as well as affinities for rat, mouse, pig, dog, and monkey glucagon receptors. Generally, the compounds had slightly less glucagon receptor affinity compared to compounds of the previous series, but this was compensated for by much improved PK profiles in both rats and dogs with high oral bioavailabilities and sustained high plasma exposures. The compounds generally showed species selectivity for glucagon receptor binding with poor affinities for the rat, mouse, rabbit, and pig receptors. However, dog and monkey glucagon receptor affinities seem to reflect the human situation. One compound of this series, 18, was tested intravenously in an anesthetized glucagon-challenged monkey model of hyperglucagonaemia and hyperglycaemia and was shown dose-dependently to decrease glycaemia. Further, high plasma exposures and a long plasma half-life (5.2 h) were obtained.