4-[[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]amino]-2,2-dimethylbutanoic acid | 210891-15-9

• 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-[[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]amino]-2,2-dimethylbutanoic acid
• 英文别名: 4-[[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2 yl]methyl]amino]-2,2-dimethylbutanoic acid；4-[[[2'-[[(4,5-Dimethyl-3-isoxazolyl)amino]sulfonyl]4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]amino]-2,2-dimethylbutanoic acid；4-[[2-[2-[(4,5-Dimethyl-1,2-oxazol-3-yl)sulfamoyl]phenyl]-5-(1,3-oxazol-2-yl)phenyl]methylamino]-2,2-dimethylbutanoic acid
• CAS: 210891-15-9
• 化学式: C₂₇H₃₀N₄O₆S
• 分子量: 538.624
• InChiKey: RWSWTPSGSWLTCF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  38
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  156
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  4-[[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]amino]-2,2-dimethylbutanoic acid 在 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以1.47 g的产率得到N-(4,5-dimethyl-3-isoxazolyl)-2'-[(3,3-dimethyl-2-oxo-1-pyrrolidinyl)methyl]-4'-(2-oxazolyl)[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：

  2-溴苯磺酰氯 在 吡啶 、 盐酸 、 4-二甲氨基吡啶 、 四(三苯基膦)钯 、 正丁基锂 、 sodium acetate 、 三乙酰氧基硼氢化钠 、 sodium hydride 、 sodium carbonate 、 溶剂黄146 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 正戊烷 为溶剂， 反应 15.34h， 生成 4-[[[2'-[[(4,5-dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1'-biphenyl]-2-yl]methyl]amino]-2,2-dimethylbutanoic acid
  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

文献信息

• ENDOTHELIN ANTAGONISTS: N- 2'- (4,5-DIMETHYL-3-ISOXAZOLYL) AMINO]SULFONYL]-4-(2-OXAZOLYL) 1,1'-BIPHENYL]-2-YL]METHYL] -N,3,3-TRIMETHYLBUTANAMIDE AND N-(4,5-DIMETHYL-3-ISOXAZOLYL) -2'- (3,3-DIMETHYL-2-OXO-1-PYRROLIDINYL) METHYL] -4'-(2-OXAZOLYL) 1,1'-BIPHENYL]-2-SULFONAMIDE AND SALTS THEREOF
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0996618B1

  公开（公告）日：2003-11-12
• US6043265A
  申请人：——

  公开号：US6043265A

  公开（公告）日：2000-03-28