1-{4-[2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl]piperazin-1-yl}ethanone | 958258-25-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 1-{4-[2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl]piperazin-1-yl}ethanone
• 英文别名: 1-[4-[2-[4-Amino-2-(2-methylpyrazol-3-yl)phenoxy]ethyl]piperazin-1-yl]ethanone
• CAS: 958258-25-8
• 化学式: C₁₈H₂₅N₅O₂
• 分子量: 343.429
• InChiKey: UJVOYTBCDHQBJJ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  76.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-{4-[2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl]piperazin-1-yl}ethanone 、 3-(三氟甲基)苯甲酰氯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 0.33h， 生成 N-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]-3-(1-methyl-1H-pyrazol-5-yl)phenyl}-3-(trifluoromethyl)benzamide
  参考文献：
  名称：

  Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

  摘要：

  Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.

  DOI：

  10.1021/jm100044a
• 作为产物：
  描述：

  1-{4-[2-(2-(1-methyl-1H-pyrazol-5-yl)-4-nitrophenoxy)ethyl]piperazin-1-yl}ethanone 在 氯化铵 、 锌 作用下， 以 四氢呋喃 、 水 为溶剂， 生成 1-{4-[2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethyl]piperazin-1-yl}ethanone
  参考文献：
  名称：

  Discovery and Structure−Activity Relationship of 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis

  摘要：

  Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.

  DOI：

  10.1021/jm100044a

文献信息

• Solubilized phenyl-pyrazole ureas as potent, selective 5-HT2A inverse-agonists and their application as antiplatelet agents
  作者：Peter I. Dosa、Sonja Strah-Pleynet、Honnappa Jayakumar、Martin Casper、Marc Decaire、Yifeng Xiong、Juerg Lehmann、Karoline Choi、Katie Elwell、Amy Wong、Robert R. Webb、John W. Adams、Juan Ramirez、Jeremy G. Richman、William Thomsen、Graeme Semple、Bradley R. Teegarden

  DOI：10.1016/j.bmcl.2009.07.073

  日期：2009.9

  Potent 5-HT2A inverse-agonists containing phenyl-pyrazole ureas with an amino side chain were identified. Optimization of this series resulted in selective compounds that proved effective in modulating 5HT-induced amplification of ADP-stimulated human platelet aggregation. (C) 2009 Elsevier Ltd. All rights reserved.
• ACETAMIDE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO
  申请人：Arena Pharmaceuticals, Inc.

  公开号：EP2051978A2

  公开（公告）日：2009-04-29
• [EN] ACETAMIDE DERIVATIVES AS MODULATORS OF THE 5-HT2A SEROTONIN RECEPTOR USEFUL FOR THE TREATMENT OF DISORDERS RELATED THERETO<br/>[FR] DÉRIVÉS D'ACÉTAMIDES UTILISÉS EN TANT QUE MODULATEURS DU RÉCEPTEUR DE LA SÉROTONINE 5-HT2A UTILISÉS POUR LE TRAITEMENT DE TROUBLES ASSOCIÉS À CE RÉCEPTEUR
  申请人：ARENA PHARM INC

  公开号：WO2007136875A2

  公开（公告）日：2007-11-29

  [EN] The present invention pertains to certain compounds of Formula (Ia) and pharmaceutical compositions thereof that modulate the activity of the 5-HT_2A serotonin receptor. Compounds and pharmaceutical compositions thereof are directed to methods useful in the treatment of platelet aggreagation, coronary artery disease, myocardial infarction, transient ischemic attack, angina, stroke, atrial fibrillation, blood clot formation, asthma or symptoms thereof, agitation or a symptom thereof, behavioral disorders, drug induced psychosis, excitative psychosis, Gilles de la Tourette's syndrome, manic disorder, organic or NOS psychosis, psychotic disorder, psychosis, acute schizophrenia, chronic schizophrenia, NOS schizophrenia and related disorders, and sleep disorders, sleep disorders, diabetic-related disorders, progressive multifocal leukoencephalopathy and the like. The present invention also relates to the methods for the treatment of 5-HT_2A serotonin receptor associated disorders in combination with other pharmaceutical agents administered separately or together.
  [FR] La présente invention concerne certains composés représentés par la formule (1a) ainsi que des compositions pharmaceutiques les contenant, lesquels modulent l'activité du récepteur de la sérotonine 5-HT_2A. Les composés et les compositions pharmaceutiques susmentionnés sont destinés à des méthodes utiles pour traiter l'agrégation plaquettaire, la coronaropathie, l'infarctus du myocarde, l'accident ischémique transitoire, l'angine, l'accident vasculaire cérébral, la fibrillation auriculaire, la coagulation sanguine, l'asthme ou l'un de ses symptômes, l'agitation ou l'un de ses symptômes, les troubles du comportement, la psychose induite par les médicaments, la psychose avec excitation, le syndrôme de Tourette, le trouble maniaque, la psychose organique ou non spécifiée, le trouble psychotique, la psychose, la schizophrénie aigue, la schizophrénie chronique, la schizophrénie non spécifiée, et les troubles apparentés, les troubles du sommeil, les troubles liés au diabète, la leucoencéphalopathie multifocale progressive et les troubles similaires. Cette invention concerne également des méthodes utiles pour le traitement de troubles associés au récepteur de la sérotonine 5-HT_2A conjointement avec d'autres agents pharmaceutiques administrés séparément ou ensemble.
• Discovery and Structure−Activity Relationship of 3-Methoxy-<i>N</i>-(3-(1-methyl-1<i>H</i>-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide (APD791): A Highly Selective 5-Hydroxytryptamine_2A Receptor Inverse Agonist for the Treatment of Arterial Thrombosis
  作者：Yifeng Xiong、Bradley R. Teegarden、Jin-Sun Karoline Choi、Sonja Strah-Pleynet、Marc Decaire、Honnappa Jayakumar、Peter I. Dosa、Martin D. Casper、Lan Pham、Konrad Feichtinger、Brett Ullman、John Adams、Diane Yuskin、John Frazer、Michael Morgan、Abu Sadeque、Weichao Chen、Robert R. Webb、Daniel T. Connolly、Graeme Semple、Hussien Al-Shamma

  DOI：10.1021/jm100044a

  日期：2010.6.10

  Serotonin, which is stored in platelets and is released during thrombosis, activates platelets via the 5-HT2A receptor. 5-HT2A receptor inverse agonists thus represent a potential new class of antithrombotic agents. Our medicinal program began with known compounds that displayed binding affinity for the recombinant 5-HT2A receptor, but which had poor activity when tested in human plasma platelet inhibition assays. We herein describe a series of phenyl pyrazole inverse agonists optimized for selectivity, aqueous solubility, antiplatelet activity, low hERG activity, and good pharmacokinetic properties, resulting in the discovery of 10k (APD791). 10k inhibited serotonin-amplified human platelet aggregation with an IC50 = 8.7 nM and had negligible binding affinity for the closely related 5-HT2B and 5-HT2C receptors. 10k was orally bioavailable in rats, dogs, and monkeys and had an acceptable safety profile. As a result, 10k was selected further evaluation and advanced into clinical development as a potential treatment for arterial thrombosis.