N-({4-[(1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(propan-2-yl)naphthalen-2-yl]-1H-pyrazol-1-yl}ethyl]phenyl}carbonyl)-β-alanine | 1383937-95-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: N-({4-[(1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(propan-2-yl)naphthalen-2-yl]-1H-pyrazol-1-yl}ethyl]phenyl}carbonyl)-β-alanine
• 英文别名: 3-[[4-[(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-propan-2-ylnaphthalen-2-yl)pyrazol-1-yl]ethyl]benzoyl]amino]propanoic acid
• CAS: 1383937-95-8
• 化学式: C₃₄H₃₁Cl₂N₃O₃
• 分子量: 600.544
• InChiKey: HHKKVYXTKFAECF-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8
• 重原子数：
  42
• 可旋转键数：
  9
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  84.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  3-(3,5-二氯苯基)-3-氧代-丙酸乙酯 在 四(三苯基膦)钯 、 溶剂黄146 、 三乙胺 、 三氟乙酸 、 sodium hydroxide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙二醇二甲醚 、 二氯甲烷 为溶剂， 反应 9.17h， 生成 N-({4-[(1S)-1-{3-(3,5-dichlorophenyl)-5-[6-(propan-2-yl)naphthalen-2-yl]-1H-pyrazol-1-yl}ethyl]phenyl}carbonyl)-β-alanine
  参考文献：
  名称：

  Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

  摘要：

  A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl) -5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)-carbonyl]-beta-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC50 of 6.6 nM) and functional cAMP activity (IC50 of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC50 values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

  DOI：

  10.1021/jm300579z

文献信息

• Discovery of a Novel Glucagon Receptor Antagonist <i>N</i>-[(4-{(1<i>S</i>)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1<i>H</i>-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes
  作者：Yusheng Xiong、Jian Guo、Mari R. Candelore、Rui Liang、Corey Miller、Qing Dallas-Yang、Guoqiang Jiang、Peggy E. McCann、Sajjad A. Qureshi、Xinchun Tong、Shiyao Sherrie Xu、Jackie Shang、Stella H. Vincent、Laurie M. Tota、Michael J. Wright、Xiaodong Yang、Bei B. Zhang、James R. Tata、Emma R. Parmee

  DOI：10.1021/jm300579z

  日期：2012.7.12

  A potent, selective glucagon receptor antagonist 9m, N-[(4-(1S)-1-[3-(3,5-dichlorophenyl) -5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)-carbonyl]-beta-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC50 of 6.6 nM) and functional cAMP activity (IC50 of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC50 values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.