(+/-)-4-[5-(4-fluorophenyl)-3-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid | 1242144-83-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并恶唑类
• 英文名称: (+/-)-4-[5-(4-fluorophenyl)-3-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
• 英文别名: 4-[3-(4-fluorophenyl)-5-(2-oxo-3H-1,3-benzoxazol-6-yl)-3,4-dihydropyrazol-2-yl]benzoic acid
• CAS: 1242144-83-7
• 化学式: C₂₃H₁₆FN₃O₄
• 分子量: 417.396
• InChiKey: WEJFKQDHBKGIHH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  91.2
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  ethyl 4-[5-(4-fluorophenyl)-3-(2-oxo-2,3-dihydrobenzoxazol-6-yl)-4,5-dihydropyrazol-1-yl]benzoate 在 水 、 potassium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 96.0h， 以65%的产率得到(+/-)-4-[5-(4-fluorophenyl)-3-(2-oxo-2,3-dihydro-1,3-benzoxazol-6-yl)-4,5-dihydro-1H-pyrazol-1-yl]benzoic acid
  参考文献：
  名称：

  Discovery of (3S,3aR)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy

  摘要：

  We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (M R) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.

  DOI：

  10.1021/jm100505n

文献信息

• Discovery of (3<i>S</i>,3a<i>R</i>)-2-(3-Chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2<i>H</i>-benzo[<i>g</i>]indazole-7-carboxylic Acid (PF-3882845), an Orally Efficacious Mineralocorticoid Receptor (MR) Antagonist for Hypertension and Nephropathy
  作者：Marvin J. Meyers、Graciela B. Arhancet、Susan L. Hockerman、Xiangyang Chen、Scott A. Long、Matthew W. Mahoney、Joseph R. Rico、Danny J. Garland、James. R. Blinn、Joe T. Collins、Shengtian Yang、Horng-Chih Huang、Kevin F. McGee、Jay M. Wendling、Jessica D. Dietz、Maria A. Payne、Bruce L. Homer、Marcia I. Heron、David B. Reitz、Xiao Hu

  DOI：10.1021/jm100505n

  日期：2010.8.26

  We have discovered a novel class of nonsteroidal pyrazoline antagonists of the mineralocorticoid receptor (M R) that show excellent potency and selectivity against other nuclear receptors. Early analogues were poorly soluble and had a propensity to inhibit the hERG channel. Remarkably, both of these challenges were overcome by incorporation of a single carboxylate moiety. Structural modification of carboxylate-containing lead R-4g with a wide range of substituents at each position of the pyrazoline ring resulted in R-12o, which shows excellent activity against MR and reasonable pharmacokinetic profile. Introduction of conformational restriction led to a novel series characterized by exquisite potency and favorable steroid receptor selectivity and pharmacokinetic profile. Oral dosing of 3S,3aR-27d (PF-3882845) in the Dahl salt sensitive preclinical model of salt-induced hypertension and nephropathy showed blood pressure attenuation significantly greater than that with eplerenone, reduction in urinary albumin, and renal protection. As a result of these findings, 3S,3aR-27d was advanced to clinical studies.