1-[[1-(4-氯苯基)吡唑-4-基]甲基]-4-苯基哌嗪 | 591774-47-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 中文名称: 1-[[1-(4-氯苯基)吡唑-4-基]甲基]-4-苯基哌嗪
• 英文名称: LASSBio 579
• 英文别名: 1-((1-(4-chlorophenyl)-1H-pyrazol-4-yl)methyl)-4-phenylpiperazine;；1-[(1-(4-Chlorophenyl)-1H-pyrazol-4-yl)methyl]-4-phenylpiperazine；1-[[1-(4-chlorophenyl)pyrazol-4-yl]methyl]-4-phenylpiperazine
• CAS: 591774-47-9
• 化学式: C₂₀H₂₁ClN₄
• 分子量: 352.867
• InChiKey: MHJWMIITIMUUKU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  25
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  24.3
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-[[1-(4-氯苯基)吡唑-4-基]甲基]-4-苯基哌嗪 在 Cunninghamella echinulata ATCC 9244 、 liquid potato dextrose soy medium 作用下， 反应 96.0h， 生成 4-[4-[[1-(4-Chlorophenyl)pyrazol-4-yl]methyl]piperazin-1-yl]phenol
  参考文献：
  名称：

  Biotransformation of LASSBio-579 and pharmacological evaluation of p -hydroxylated metabolite a N -phenylpiperazine antipsychotic lead compound

  摘要：

  Using a combination of docking and molecular dynamics simulations, we predicted that p-hydroxylation by CYP1A2 would be the main metabolic pathway for the 1-[1-(4-chlorophenyl)-1H-4pyrazolylmethyl]phenylhexahydropiperazine, LASSBio-579 (3). As the result of a screening process with strains of filamentous fungi, Cunninghamella echinulata ATCC 9244 was chosen to scale up the preparation of the p-hydroxylated metabolite (4). About 30 min after i.p. administration of (3) to rats was identified as the p-hydroxylated metabolite, confirming our in silico previsions. Chemical synthesis of the metabolite was performed and allowed its pharmacological evaluation in binding assays revealing its high affinity for D2 and D4 receptors, indicating that this metabolite should participate to the antipsychotic effect of (3) in vivo. Furthermore, we report here that both (3) and its p-hydroxylated metabolite (4) have a much lower affinity than clozapine for two receptors involved in adverse reactions. Voltammetric assays were useful to understand the redox profile of (3). (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.08.011
• 作为产物：
  描述：

  4-氯苯肼 在 盐酸 、 sodium cyanoborohydride 、 溶剂黄146 、 三氯氧磷 作用下， 以 甲醇 、 乙醇 为溶剂， 反应 13.0h， 生成 1-[[1-(4-氯苯基)吡唑-4-基]甲基]-4-苯基哌嗪
  参考文献：
  名称：

  Design, synthesis and pharmacological profile of novel dopamine D2 receptor ligands

  摘要：

  The present study describes the synthesis and pharmacological profile of three novel heterocyclic compounds originally designed, on the basis of bioisosterism, as dopamine D2 receptor ligands: 1-[1-(4-chlorophenyl)-1H-pyrazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-579), 1-phenyl-4-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-piperazine (LASSBio-580) and]-[1-(4-chloro-phenyl)-1H-[1,2,3]triazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-581). Binding studies performed on brain homogenate indicated that all three compounds bind selectively to D2 receptors. In addition, electrophysiological studies carried out in cultured hippocampal neurons suggested that LASSBio-579 and 581 act as D2 agonists, whereas LASSBio-580 acts as a D2 antagonist. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(03)00487-5

文献信息

• Searching for multi-target antipsychotics: Discovery of orally active heterocyclic N-phenylpiperazine ligands of D2-like and 5-HT1A receptors
  作者：Gilda Neves、Ricardo Menegatti、Camila B. Antonio、Luiza R. Grazziottin、Renan O. Vieira、Stela M.K. Rates、François Noël、Eliezer J. Barreiro、Carlos A.M. Fraga

  DOI：10.1016/j.bmc.2010.01.040

  日期：2010.3

  We described herein the design, synthesis, and pharmacological evaluation of N-phenylpiperazine heterocyclic derivatives as multi-target compounds potentially useful for the treatment of schizophrenia. The isosteric replacement of the heterocyclic ring at the biaryl motif generating pyrazole, 1,2,3-triazole, and 2-methylimidazole[1,2-a]pyridine derivatives resulted in 21 analogues with different substitutions at the para-biaryl and para-phenylpiperazine positions. Among the compounds prepared, 4 (LASSBio-579) and 10 (LASSBio-664) exhibited an adequate binding profile and a potential for schizophrenia positive symptoms treatment without cataleptogenic effects. Structural features of this molecular scaffold are discussed regarding binding affinity and selectivity for D-2-like, 5-HT1A, and 5-HT2A receptors. (C) 2010 Elsevier Ltd. All rights reserved.
• [EN] USE OF N-PHENYLPIPERAZINE DERIVATIVES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM<br/>[FR] UTILISATION DE DERIVES DE N-PHENYLPIPERAZINE ET COMPOSITIONS PHARMACEUTIQUES CONTENANT CES DERNIERS
  申请人：UNIV RIO DE JANEIRO

  公开号：WO2006024121A1

  公开（公告）日：2006-03-09

  This invention covers new N-phenylpiperazines derivatives and pharmaceutical compositions encompassing them, with these new structural clozapine derivatives ab a to act in dopamine andlor central-action pathways; these compounds were demonstrated to be useful in the treatment of erectile dysfunction and also useful as antipsychotics, with the advantages of not causing the side-effects typical of clozapine; they result in a lower incidence of catatonia when compared with haloperidol, another antipsychotic agent, and did not present any depressor effect on the central nervous system; the molecules also presented a hypothermic effect, which may be useful in the treatment of conditions presenting hyperthe~mia.
• Design, synthesis and pharmacological profile of novel dopamine D2 receptor ligands
  作者：Ricardo Menegatti、Anna C Cunha、Vı́tor F Ferreira、Edna F.R Perreira、Ahmed El-Nabawi、Amira T Eldefrawi、Edson X Albuquerque、Gilda Neves、Stela M.K Rates、Carlos A.M Fraga、Eliezer J Barreiro

  DOI：10.1016/s0968-0896(03)00487-5

  日期：2003.11

  The present study describes the synthesis and pharmacological profile of three novel heterocyclic compounds originally designed, on the basis of bioisosterism, as dopamine D2 receptor ligands: 1-[1-(4-chlorophenyl)-1H-pyrazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-579), 1-phenyl-4-(1-phenyl-1H-[1,2,3]triazol-4-ylmethyl)-piperazine (LASSBio-580) and]-[1-(4-chloro-phenyl)-1H-[1,2,3]triazol-4-ylmethyl]-4-phenyl-piperazine (LASSBio-581). Binding studies performed on brain homogenate indicated that all three compounds bind selectively to D2 receptors. In addition, electrophysiological studies carried out in cultured hippocampal neurons suggested that LASSBio-579 and 581 act as D2 agonists, whereas LASSBio-580 acts as a D2 antagonist. (C) 2003 Elsevier Ltd. All rights reserved.
• Biotransformation of LASSBio-579 and pharmacological evaluation of p -hydroxylated metabolite a N -phenylpiperazine antipsychotic lead compound
  作者：Tatiana F. Gomes、Thais E.T. Pompeu、Daniel A. Rodrigues、François Noël、Ricardo Menegatti、Carolina H. Andrade、José R. Sabino、Eric S. Gil、Teresa Dalla Costa、Andresa H. Betti、Camila B. Antonio、Stela M.K. Rates、Carlos A.M. Fraga、Eliezer J. Barreiro、Valéria de Oliveira

  DOI：10.1016/j.ejmech.2012.08.011

  日期：2013.4

  Using a combination of docking and molecular dynamics simulations, we predicted that p-hydroxylation by CYP1A2 would be the main metabolic pathway for the 1-[1-(4-chlorophenyl)-1H-4pyrazolylmethyl]phenylhexahydropiperazine, LASSBio-579 (3). As the result of a screening process with strains of filamentous fungi, Cunninghamella echinulata ATCC 9244 was chosen to scale up the preparation of the p-hydroxylated metabolite (4). About 30 min after i.p. administration of (3) to rats was identified as the p-hydroxylated metabolite, confirming our in silico previsions. Chemical synthesis of the metabolite was performed and allowed its pharmacological evaluation in binding assays revealing its high affinity for D2 and D4 receptors, indicating that this metabolite should participate to the antipsychotic effect of (3) in vivo. Furthermore, we report here that both (3) and its p-hydroxylated metabolite (4) have a much lower affinity than clozapine for two receptors involved in adverse reactions. Voltammetric assays were useful to understand the redox profile of (3). (C) 2012 Elsevier Masson SAS. All rights reserved.