4-[(4S,5S)-1-(3-chloro-4-cyanophenyl)-5-cyclopentyl-4-methyl-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxybenzoic acid | 1242145-20-5

• 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-[(4S,5S)-1-(3-chloro-4-cyanophenyl)-5-cyclopentyl-4-methyl-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxybenzoic acid
• 英文别名: 4-[(3S,4S)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-4-methyl-3,4-dihydropyrazol-5-yl]-2-methoxybenzoic acid
• CAS: 1242145-20-5
• 化学式: C₂₄H₂₄ClN₃O₃
• 分子量: 437.926
• InChiKey: XESZSROXZVELDI-QKFKETGDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  85.9
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-[(5R)-1-(3-chloro-4-cyanophenyl)-5-cyclopentyl-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxybenzoic acid 、 碘甲烷 在 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 正己烷 为溶剂， 反应 3.5h， 以60%的产率得到4-[(4S,5S)-1-(3-chloro-4-cyanophenyl)-5-cyclopentyl-4-methyl-4,5-dihydro-1H-pyrazol-3-yl]-2-methoxybenzoic 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