N-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[2-(hydroxymethyl)-4-(1,3-oxazol-2-yl)phenyl]-N-(2-methoxyethoxymethyl)benzenesulfonamide | 195447-19-9

• 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: N-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[2-(hydroxymethyl)-4-(1,3-oxazol-2-yl)phenyl]-N-(2-methoxyethoxymethyl)benzenesulfonamide
• CAS: 195447-19-9
• 化学式: C₂₅H₂₇N₃O₇S
• 分子量: 513.571
• InChiKey: MYHBGIHJZGYBNG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  137
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  N-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[2-(hydroxymethyl)-4-(1,3-oxazol-2-yl)phenyl]-N-(2-methoxyethoxymethyl)benzenesulfonamide 在 四溴化碳 、 sodium hydride 、 三苯基膦 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 14.5h， 生成 N-(3,4-Dimethyl-5-isoxazolyl)-N-[(2-methoxyethoxy)methyl]-4'-(2-oxazolyl)-2'-(phenoxymethyl)[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 作用下， 以 甲醇 为溶剂， 反应 2.5h， 生成 N-(3,4-dimethyl-1,2-oxazol-5-yl)-2-[2-(hydroxymethyl)-4-(1,3-oxazol-2-yl)phenyl]-N-(2-methoxyethoxymethyl)benzenesulfonamide
  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

• SUBSTITUTED BIPHENYL ISOXAZOLE SULFONAMIDES
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：EP0921800B1

  公开（公告）日：2004-04-14
• US5846990A
  申请人：——

  公开号：US5846990A

  公开（公告）日：1998-12-08
• Biphenylsulfonamide Endothelin Receptor Antagonists. 4. Discovery of <i>N</i>-[[2‘-[[(4,5-Dimethyl-3-isoxazolyl)amino]sulfonyl]-4-(2-oxazolyl)[1,1‘-biphenyl]- 2-yl]methyl]-<i>N</i>,3,3-trimethylbutanamide (BMS-207940), A Highly Potent and Orally Active ET_A Selective Antagonist
  作者：Natesan Murugesan、Zhengxiang Gu、Steven Spergel、Marian Young、Ping Chen、Arvind Mathur、Leslie Leith、Mark Hermsmeier、Eddie C.-K. Liu、Rongan Zhang、Eileen Bird、Tom Waldron、Anthony Marino、Barry Koplowitz、W. Griffith Humphreys、Saeho Chong、Richard A. Morrison、Maria L. Webb、Suzanne Moreland、Nick Trippodo、Joel C. Barrish

  DOI：10.1021/jm020289q

  日期：2003.1.1

  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.