(R)-1-{4-[2-((S)-1-amino-2-methyl-propyl)-6-fluoro-phenyl]-piperazin-1-yl}-3-(4-chloro-phenyl)-2-methyl-propan-1-one | 1040411-48-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: (R)-1-{4-[2-((S)-1-amino-2-methyl-propyl)-6-fluoro-phenyl]-piperazin-1-yl}-3-(4-chloro-phenyl)-2-methyl-propan-1-one
• 英文别名: 1-{2-[(1S)-Amino-2-methylpropyl]-6-fluorophenyl}-4-[(2R)-methyl-3-(4-chlorophenyl)propionyl]-piperazine；(2R)-1-[4-[2-[(1S)-1-amino-2-methylpropyl]-6-fluorophenyl]piperazin-1-yl]-3-(4-chlorophenyl)-2-methylpropan-1-one
• CAS: 1040411-48-0
• 化学式: C₂₄H₃₁ClFN₃O
• 分子量: 431.981
• InChiKey: BBCHXERJCYULCI-VGSWGCGISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  49.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-1-{4-[2-((S)-1-amino-2-methyl-propyl)-6-fluoro-phenyl]-piperazin-1-yl}-3-(4-chloro-phenyl)-2-methyl-propan-1-one 、 叔丁氧羰酰基肌氨酸 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 8.0h， 生成
  参考文献：
  名称：

  Pharmacological and pharmacokinetic characterization of 2-piperazine-α-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists

  摘要：

  A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8 - 12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1 mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20 mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.03.072
• 作为产物：
  描述：

  1-{2-[(1S)-1-[(S)-(tert-butylsulfinyl)amino]-2-methylpropyl]-6-fluorophenyl}-4-[(2R)-2-methyl-3-(4-chlorophenyl)propionyl]piperazine 在 盐酸 作用下， 以 甲醇 为溶剂， 反应 1.0h， 生成 (R)-1-{4-[2-((S)-1-amino-2-methyl-propyl)-6-fluoro-phenyl]-piperazin-1-yl}-3-(4-chloro-phenyl)-2-methyl-propan-1-one
  参考文献：
  名称：

  Pharmacological and pharmacokinetic characterization of 2-piperazine-α-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists

  摘要：

  A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8 - 12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1 mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20 mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.03.072

文献信息

• Ligands of melanocortin receptors and compositions and methods related thereto
  申请人：Tucci C. Fabio

  公开号：US20050119252A1

  公开（公告）日：2005-06-02

  Compounds which function as melanocortin receptor ligands and having utility in the treatment of melanocortin receptor-based disorders. The compounds have the following structure (I): including stereoisomers, prodrugs, and pharmaceutically acceptable salts thereof, wherein m, n, q, s, R 1 , R 1a , R 1b , R 2 , R 3 , R 4a , R 4b , R 5a , R 5b , X 1 , X 2 , X 3 , X 4 and Ar are as defined herein. Pharmaceutical compositions containing a compound of structure (I), as well as methods relating to the use thereof, are also disclosed.

  这是一种功能为黑素皮质素受体配体的化合物，可用于治疗基于黑素皮质素受体的疾病。该化合物具有以下结构（I）：包括立体异构体，前药和其药学上可接受的盐，其中m，n，q，s，R1，R1a，R1b，R2，R3，R4a，R4b，R5a，R5b，X1，X2，X3，X4和Ar的定义如本文所述。还公开了含有结构（I）化合物的药物组成物，以及与其使用相关的方法。
• [EN] LIGANDS OF MELANOCORTIN RECEPTORS AND COMPOSITIONS AND METHODS RELATED THERETO<br/>[FR] LIGANDS DE RECEPTEURS DE LA MELANOCORTINE, COMPOSITIONS ET PROCEDES ASSOCIES
  申请人：NEUROCRINE BIOSCIENCES INC

  公开号：WO2005042516A3

  公开（公告）日：2005-12-01
• Pharmacological and pharmacokinetic characterization of 2-piperazine-α-isopropyl benzylamine derivatives as melanocortin-4 receptor antagonists
  作者：Chen Chen、Fabio C. Tucci、Wanlong Jiang、Joe A. Tran、Beth A. Fleck、Sam R. Hoare、Jenny Wen、Takung Chen、Michael Johns、Stacy Markison、Alan C. Foster、Dragan Marinkovic、Caroline W. Chen、Melissa Arellano、John Harman、John Saunders、Haig Bozigian、Daniel Marks

  DOI：10.1016/j.bmc.2008.03.072

  日期：2008.5

  A series of 2-piperazine-alpha-isopropylbenzylamine derivatives were synthesized and characterized as melanocortin-4 receptor (MC4R) antagonists. Attaching an amino acid to benzylamines 7 significantly increased their binding affinity, and the resulting compounds 8 - 12 bound selectively to MC4R over other melanocortin receptor subtypes and behaved as functional antagonists. These compounds were also studied for their permeability using Caco-2 cell monolayers and metabolic stability in human liver microsomes. Most compounds exhibited low permeability and high efflux ratio possibly due to their high molecular weights. They also showed moderate metabolic stability which might be associated with their moderate to high lipophilicity. Pharmacokinetic properties of these MC4R antagonists, including brain penetration, were studied in mice after oral and intravenous administrations. Two compounds identified to possess high binding affinity and selectivity, 10d and 11d, were studied in a murine cachexia model. After intraperitoneal (ip) administration of 1 mg/kg dose, mice treated with 10d had significantly more food intake and weight gain than the control animals, demonstrating efficacy by blocking the MC4 receptor. Similar in vivo effects were also observed when 11d was dosed orally at 20 mg/kg. These results provide further evidence that a potent and selective MC4R antagonist has potential in the treatment of cancer cachexia. (C) 2008 Elsevier Ltd. All rights reserved.