2-[2-[2-[(3,4-dimethyl-1,2-oxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]-N,N-dimethylacetamide | 195447-16-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-[2-[2-[(3,4-dimethyl-1,2-oxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]-N,N-dimethylacetamide
• CAS: 195447-16-6
• 化学式: C₂₈H₃₂N₄O₇S
• 分子量: 568.651
• InChiKey: HCFSHSSUGFDKCU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  40
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  137
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  2-[2-[2-[(3,4-dimethyl-1,2-oxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]-N,N-dimethylacetamide 在 三甲基氯硅烷 、 sodium iodide 作用下， 以 乙腈 为溶剂， 反应 3.0h， 以62%的产率得到2'-[[(3,4-Dimethyl-5-isoxazolyl)amino]sulfonyl]-N,N-dimethyl-4-(2-oxazolyl)[1,1'-biphenyl]-2-acetamide
  参考文献：
  名称：

  Biphenylsulfonamide Endothelin Receptor Antagonists. 4. Discovery of N-[[2‘-[[(4,5-Dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1‘-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), A Highly Potent and Orally Active ET_A Selective Antagonist

  摘要：

  We have previously disclosed the selective ETA receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ETA receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent lleading to 16a (BMS-207940). Compound 16a is an extremely potent (ETAKi = 10 pM) and selective (80000-fold for ETA vs ETB) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 mumol/kg, 16a displays enhanced duration relative to 1.

  DOI：

  10.1021/jm020289q
• 作为产物：
  描述：

  N-(3,4-Dimethyl-5-isoxazolyl)-2'-formyl-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)-[1,1'-biphenyl]-2-sulfonamide 在 sodium chlorite 、 草酰氯 、 氨基磺酸 、 对甲苯磺酸 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 硝基甲烷 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.36h， 生成 2-[2-[2-[(3,4-dimethyl-1,2-oxazol-5-yl)-(2-methoxyethoxymethyl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]-N,N-dimethylacetamide
  参考文献：
  名称：

  Biphenylsulfonamide Endothelin Receptor Antagonists. 4. Discovery of N-[[2‘-[[(4,5-Dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1‘-biphenyl]- 2-yl]methyl]-N,3,3-trimethylbutanamide (BMS-207940), A Highly Potent and Orally Active ET_A Selective Antagonist

  摘要：

  We have previously disclosed the selective ETA receptor antagonist N-(3,4-dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)[1,1'-biphenyl]-2-sulfonamide (1, BMS-193884) as a clinical development candidate. Additional SAR studies at the 2'-position of 1 led to the identification of several analogues with improved binding affinity as well as selectivity for the ETA receptor. Following the discovery that a 3-amino-isoxazole group displays significantly improved metabolic stability in comparison to its 5-regioisomer, the 3-amino-isoxazole group was combined with the optimal 2'-substituent lleading to 16a (BMS-207940). Compound 16a is an extremely potent (ETAKi = 10 pM) and selective (80000-fold for ETA vs ETB) antagonist. It is also 150-fold more potent and >6-fold more selective than 1. The bioavailability of 16a was 100% in rats and the systemic clearance and volume of distribution are higher than that of 1. In rats, intravenous 16a blocks big ET pressor responses with 30-fold greater potency than 1. After oral dosing at 3 mumol/kg, 16a displays enhanced duration relative to 1.

  DOI：

  10.1021/jm020289q