4-(diphenylhydroxymethyl)-3-isopropoxy-5-(1-methoxycarbonyl-4-piperidyl)isoxazole | 439944-74-8

• 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-(diphenylhydroxymethyl)-3-isopropoxy-5-(1-methoxycarbonyl-4-piperidyl)isoxazole
• 英文别名: Methyl 4-[4-[hydroxy(diphenyl)methyl]-3-propan-2-yloxy-1,2-oxazol-5-yl]piperidine-1-carboxylate
• CAS: 439944-74-8
• 化学式: C₂₆H₃₀N₂O₅
• 分子量: 450.535
• InChiKey: XGKPKTDDYHRYIU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  85
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(diphenylhydroxymethyl)-3-isopropoxy-5-(1-methoxycarbonyl-4-piperidyl)isoxazole 在 三乙基硅烷 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 以78%的产率得到4-(diphenylmethyl)-3-isopropoxy-5-(1-methoxycarbonyl-4-piperidyl)isoxazole
  参考文献：
  名称：

  Novel Class of Potent 4-Arylalkyl Substituted 3-Isoxazolol GABA_A Antagonists:  Synthesis, Pharmacology, and Molecular Modeling

  摘要：

  A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K-i = 9.1 muM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K-i = 0.074 muM and K-i = 0.049 muM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC50 = 0.37 muM and IC50 = 0.02 muM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC50 = 0.24 muM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED50 = 0.024 mumol/kg) and 7s (ED50 = 0.21 mumol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity.

  DOI：

  10.1021/jm020027o
• 作为产物：
  描述：

  5-(1-methoxycarbonyl-4-piperidyl)-3-isoxazolol 在 乙基氯化镁 、 一氯化碘 、 potassium carbonate 、 溶剂黄146 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 85.5h， 生成 4-(diphenylhydroxymethyl)-3-isopropoxy-5-(1-methoxycarbonyl-4-piperidyl)isoxazole
  参考文献：
  名称：

  Novel Class of Potent 4-Arylalkyl Substituted 3-Isoxazolol GABA_A Antagonists:  Synthesis, Pharmacology, and Molecular Modeling

  摘要：

  A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K-i = 9.1 muM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K-i = 0.074 muM and K-i = 0.049 muM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC50 = 0.37 muM and IC50 = 0.02 muM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC50 = 0.24 muM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED50 = 0.024 mumol/kg) and 7s (ED50 = 0.21 mumol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity.

  DOI：

  10.1021/jm020027o

文献信息

• Novel Class of Potent 4-Arylalkyl Substituted 3-Isoxazolol GABA_A Antagonists:  Synthesis, Pharmacology, and Molecular Modeling
  作者：Bente Frølund、Anne T. Jørgensen、Lena Tagmose、Tine B. Stensbøl、Henrik T. Vestergaard、Christine Engblom、Uffe Kristiansen、Connie Sanchez、Povl Krogsgaard-Larsen、Tommy Liljefors

  DOI：10.1021/jm020027o

  日期：2002.6.1

  A number of analogues of the low-efficacy partial GABA(A) agonist 5-(4-piperidyl)-3-isoxazolol (4-PIOL, 5), in which the 4-position of the 3-isoxazolol ring was substituted by different groups, were synthesized and tested as GABA(A) receptor ligands. Substituents of different size and structural flexibility such as alkyl, phenylalkyl, diphenylalkyl, and naphthylalkyl were explored. Pharmacological characterization of the synthesized compounds was carried out using receptor binding assays and by electrophysiological experiments using whole-cell patch-clamp techniques. Whereas none of these compounds significantly affected GABA(B) receptor sites or GABA uptake, they did show affinity for the GABA(A) receptor site. While alkyl or benzyl substitution, compounds 7a-h, provided receptor affinities comparable with that of 5 (K-i = 9.1 muM), diphenylalkyl and naphthylalkyl substitution, as in compounds 7m-t, resulted in a dramatic increase in affinity relative to 5. The 3,3-diphenylpropyl and the 2-naphthylmethyl analogues, compounds 7s and 7m, respectively, showed the highest affinities of the series (K-i = 0.074 muM and K-i = 0.049 muM). In whole-cell patch-clamp recordings from cultured cerebral cortical neurons, all of the tested compounds were able to inhibit the effect of the specific GABA(A) agonist isoguvacine (1), compounds 7m and 7s showing antagonist potency (IC50 = 0.37 muM and IC50 = 0.02 muM) comparable with or markedly higher than that of the standard GABA(A) antagonist 4 (IC50 = 0.24 muM). Highly potent convulsant activity was demonstrated in mice with compounds 7m (ED50 = 0.024 mumol/kg) and 7s (ED50 = 0.21 mumol/kg) after intracerebroventricular administration, whereas no effects were found after subcutaneous administration. According to a previously proposed pharmacophore model for GABA(A) receptor agonists, a receptor cavity in the vicinity of the 4-position of the 3-isoxazolol ring in 4-PIOL exists. A molecular modeling study, based on compounds 7o,m,l,q,s, was performed to explore the dimensions and other properties of the receptor cavity. This study demonstrates the importance of the arylalkyl substituents in 7m and 7s and the considerable dimensions of this proposed receptor cavity.