4'-Oxazol-2-yl-2'-(3-trifluoromethyl-pyrazol-1-ylmethyl)-biphenyl-2-sulfonic acid (3,4-dimethyl-isoxazol-5-yl)-(2-methoxy-ethoxymethyl)-amide | 195447-53-1

• 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: 4'-Oxazol-2-yl-2'-(3-trifluoromethyl-pyrazol-1-ylmethyl)-biphenyl-2-sulfonic acid (3,4-dimethyl-isoxazol-5-yl)-(2-methoxy-ethoxymethyl)-amide
• CAS: 195447-53-1
• 化学式: C₂₉H₂₈F₃N₅O₆S
• 分子量: 631.632
• InChiKey: JVWGXFLDKPEQST-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.69
• 重原子数：
  44.0
• 可旋转键数：
  12.0
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  125.72
• 氢给体数：
  0.0
• 氢受体数：
  10.0

反应信息

• 作为反应物：
  描述：

  4'-Oxazol-2-yl-2'-(3-trifluoromethyl-pyrazol-1-ylmethyl)-biphenyl-2-sulfonic acid (3,4-dimethyl-isoxazol-5-yl)-(2-methoxy-ethoxymethyl)-amide 在 盐酸 作用下， 反应 2.5h， 生成 N-(3,4-Dimethyl-5-isoxazolyl)-4'-(2-oxazolyl)-2'-[[3-(trifluoromethyl)-1H-pyrazol-1-yl]methyl][1,1'-biphenyl]-2-sulfonamide
  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 tetrahydroborate 、 四溴化碳 、 sodium hydride 、 三苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 4'-Oxazol-2-yl-2'-(3-trifluoromethyl-pyrazol-1-ylmethyl)-biphenyl-2-sulfonic acid (3,4-dimethyl-isoxazol-5-yl)-(2-methoxy-ethoxymethyl)-amide
  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