(R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester | 385837-21-8

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester
• 英文别名: ethyl (2R)-3-[[4-[[4-cyclohexyl-N-[[3-methoxy-5-(trifluoromethyl)phenyl]carbamoyl]anilino]methyl]benzoyl]amino]-2-hydroxypropanoate
• CAS: 385837-21-8
• 化学式: C₃₄H₃₈F₃N₃O₆
• 分子量: 641.687
• InChiKey: BHJJFXPLVBEKFC-SSEXGKCCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.5
• 重原子数：
  46
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  117
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  (R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以94%的产率得到(R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid
  参考文献：
  名称：

  Novel Glucagon Receptor Antagonists with Improved Selectivity over the Glucose-Dependent Insulinotropic Polypeptide Receptor

  摘要：

  Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closeli related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a > 1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperolycemia in Sprague-Dawley rats. Furthermore. the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.

  DOI：

  10.1021/jm7015599
• 作为产物：
  描述：

  (R)-3-ethoxy-2-hydroxy-3-oxopropan-1-amine hydrochloride 、 4-[1-(cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoic acid 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 以99%的产率得到(R)-3-{4-[1-(4-cyclohexylphenyl)-3-(3-methoxy-5-trifluoromethylphenyl)ureidomethyl]benzoylamino}-2-hydroxypropionic acid ethyl ester
  参考文献：
  名称：

  Novel Glucagon Receptor Antagonists with Improved Selectivity over the Glucose-Dependent Insulinotropic Polypeptide Receptor

  摘要：

  Optimization of a new series of small molecule human glucagon receptor (hGluR) antagonists is described. In the process of optimizing glucagon receptor antagonists, we counter-screened against the closeli related human gastric inhibitory polypeptide receptor (hGIPR), and through structure activity analysis, we obtained compounds with low nanomolar affinities toward the hGluR, which were selective against the hGIPR and the human glucagon-like peptide-1 receptor (hGLP-1R). In the best cases, we obtained a >50 fold selectivity for the hGluR over the hGIPR and a > 1000 fold selectivity over the hGLP-1R. A potent and selective glucagon receptor antagonist was demonstrated to inhibit glucagon-induced glycogenolysis in primary rat hepatocytes as well as to lower glucagon-induced hyperolycemia in Sprague-Dawley rats. Furthermore. the compound was shown to lower blood glucose in the ob/ob mouse after oral dosing.

  DOI：

  10.1021/jm7015599

文献信息

• Glucagon antagonists/inverse agonists
  申请人：——

  公开号：US20020143186A1

  公开（公告）日：2002-10-03

  A novel class of compounds, which act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor the compounds may be suitable for the treatment and/or prevention of any diseases and disorders, wherein a glucagon antagonistic action is beneficial, such as hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism, such as dyslipidemia, and obesity.

  一种新型化合物类别，其作用是拮抗胰高血糖素激素对胰高血糖素受体的作用。由于这些化合物对胰高血糖素受体的拮抗作用，这些化合物可能适用于治疗和/或预防任何胰高血糖素拮抗作用有益的疾病和疾病，如高血糖症、1型糖尿病、2型糖尿病、脂质代谢紊乱疾病，如血脂异常和肥胖症。
• [EN] GLUCAGON ANTAGONISTS/INVERSE AGONISTS<br/>[FR] ANTAGONISTES/AGONISTES INVERSES DU GLUCAGON
  申请人：NOVO NORDISK AS

  公开号：WO2002000612A1

  公开（公告）日：2002-01-03

  A novel class of compounds, which act to antagonize the action of the glucagon hormone on the glucagon receptor. Owing to their antagonizing effect of the glucagon receptor the compounds may be suitable for the treatment and/or prevention of any diseases and disorders, wherein a glucagon antagonistic action is beneficial, such as hyperglycemia, Type 1 diabetes, Type 2 diabetes, disorders of the lipid metabolism and obesity.

  一种新型化合物，其作用是对抗胰高血糖素激素对胰高血糖素受体的作用。由于这些化合物对胰高血糖素受体的拮抗作用，因此这些化合物可能适用于治疗和/或预防任何需要胰高血糖素拮抗作用的疾病和障碍，例如高血糖症、1型糖尿病、2型糖尿病、脂质代谢障碍和肥胖症。
• [EN] SUBSTITUTED TRIAZOLO-PYRIDAZINE DERIVATIVES AS LIGANDS FOR GABA RECEPTORS<br/>[FR] DERIVES DE TRIAZOLO-PYRIDAZINE SUBSTITUES SERVANT DE LIGANDS POUR RECEPTEURS DE GABA
  申请人：MERCK SHARP & DOHME LIMITED

  公开号：WO1998004559A2

  公开（公告）日：1998-02-05

  (EN) A class of substituted or 7,8-ring fused 1,2,4-triazolo[4,3-b]pyridazine derivatives, possessing an optionally substituted cycloalkyl, phenyl or heteroaryl substituent at the 3-position and a substituted alkoxy moiety at the 6-position, are selective ligands for GABAA receptors, in particular having high affinity for the $g(a)2 and/or $g(a)3 subunit thereof, and are accordingly of benefit in the treatment and/or prevention of disorders of the central nervous system, including anxiety and convulsions.(FR) L"invention porte sur une catégorie de dérivés de 1,2,4-triazolo[4,3-b]pyridazine substitués ou fusionnés à 7,8 anneaux, possédant à la position (3) un substituant cycloalkyle, phényle ou hétéroaryle éventuellement substitué et, à la position (6), une fraction d"alkoxy substitué, ces dérivés étant des ligands sélectifs pour récepteurs de GABAA présentant en particulier une grande affinité pour les sous-unités $g(a)2 et/ou $g(a)3 de ceux-ci, ce qui les rend utiles pour le traitement et/ou la prévention des troubles du système nerveux central, notamment l"anxiété et les convulsions.

  一类取代的或7,8-环融合的1,2,4-三唑并[4,3-b]吡啶嘧啶衍生物，在3位具有可选取代的环烷基、苯基或杂环芳基取代基，在6位具有取代的烷氧基官能团，是GABAA受体的选择性配体，特别是具有高亲和力的$g(a)2和/或$g(a)3亚单位，因此对于治疗和/或预防中枢神经系统疾病，包括焦虑和惊厥，具有益处。
• SUBSTITUTED TRIAZOLO-PYRIDAZINE DERIVATIVES AS LIGANDS FOR GABA RECEPTORS
  申请人：MERCK SHARP & DOHME LTD.

  公开号：EP0915875A2

  公开（公告）日：1999-05-19
• GLUCAGON ANTAGONISTS/INVERSE AGONISTS
  申请人：Novo Nordisk A/S

  公开号：EP1296942A1

  公开（公告）日：2003-04-02