hexyl 4-[(2S)-5-tert-butoxy-2-([(4-chloro-6-phenylpyridin-2-yl)carbonyl]amino)-5-oxopentanoyl]piperazine-1-carboxylate | 1214284-60-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: hexyl 4-[(2S)-5-tert-butoxy-2-([(4-chloro-6-phenylpyridin-2-yl)carbonyl]amino)-5-oxopentanoyl]piperazine-1-carboxylate
• 英文别名: hexyl 4-[(2S)-2-[(4-chloro-6-phenylpyridine-2-carbonyl)amino]-5-[(2-methylpropan-2-yl)oxy]-5-oxopentanoyl]piperazine-1-carboxylate
• CAS: 1214284-60-2
• 化学式: C₃₂H₄₃ClN₄O₆
• 分子量: 615.17
• InChiKey: PVRLFAAWGDMBMW-VWLOTQADSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  43
• 可旋转键数：
  15
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  118
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  4-哌啶甲酸 、 hexyl 4-[(2S)-5-tert-butoxy-2-([(4-chloro-6-phenylpyridin-2-yl)carbonyl]amino)-5-oxopentanoyl]piperazine-1-carboxylate 在 三乙胺 作用下， 以 二甲基亚砜 为溶剂， 生成 (S)-1-(2-((5-(tert-butoxy)-1-(4-((hexyloxy)carbonyl)piperazin-1-yl)-1,5-dioxopentan-2-yl)carbamoyl)-6-phenylpyridin-4-yl)piperidine-4-carboxylic acid
  参考文献：
  名称：

  Part II: Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation

  摘要：

  Efforts to re. ne the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.12.110
• 作为产物：
  描述：

  hexyl 4-[(2S)-2-amino-5-tert-butoxy-5-oxopentanoyl]piperazine-1-carboxylate 、 4-氯-6-苯基吡啶-2-羧酸 在 N-甲基吗啉 、 1-羟基苯并三唑 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.0h， 以65%的产率得到hexyl 4-[(2S)-5-tert-butoxy-2-([(4-chloro-6-phenylpyridin-2-yl)carbonyl]amino)-5-oxopentanoyl]piperazine-1-carboxylate
  参考文献：
  名称：

  Piperazinyl Glutamate Pyridines as Potent Orally Bioavailable P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation

  摘要：

  Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation its measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position or the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)4-[({4-[4-(methoxymethyl)piperdin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-{4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavallability. Compound 47s was selected for further preclinical evaluations.

  DOI：

  10.1021/jm901518t

文献信息

• Piperazinyl Glutamate Pyridines as Potent Orally Bioavailable P2Y₁₂ Antagonists for Inhibition of Platelet Aggregation
  作者：John J. Parlow、Mary W. Burney、Brenda L. Case、Thomas J. Girard、Kerri A. Hall、Peter K. Harris、Ronald R. Hiebsch、Rita M. Huff、Rhonda M. Lachance、Deborah A. Mischke、Stephen R. Rapp、Rhonda S. Woerndle、Michael D. Ennis

  DOI：10.1021/jm901518t

  日期：2010.3.11

  Polymer-assisted solution-phase (PASP) parallel library synthesis was used to discover a piperazinyl glutamate pyridine as a P2Y(12) antagonist. Exploitation of this lead provided compounds with excellent inhibition of platelet aggregation its measured in a human platelet rich plasma (PRP) assay. Pharmacokinetic and physiochemical properties were optimized through modifications at the 4-position or the pyridine ring and the terminal nitrogen of the piperazine ring, leading to compound (4S)4-[(4-[4-(methoxymethyl)piperdin-1-yl]-6-phenylpyridin-2-yl}carbonyl)amino]-5-oxo-5-4-[(pentyloxy)carbonyl]piperazin-1-yl}pentanoic acid 47s with good human PRP potency, selectivity, in vivo efficacy, and oral bioavallability. Compound 47s was selected for further preclinical evaluations.
• Part II: Piperazinyl-glutamate-pyridines as potent orally bioavailable P2Y12 antagonists for inhibition of platelet aggregation
  作者：John J. Parlow、Mary W. Burney、Brenda L. Case、Thomas J. Girard、Kerri A. Hall、Peter K. Harris、Ronald R. Hiebsch、Rita M. Huff、Rhonda M. Lachance、Deborah A. Mischke、Stephen R. Rapp、Rhonda S. Woerndle、Michael D. Ennis

  DOI：10.1016/j.bmcl.2009.12.110

  日期：2010.2

  Efforts to re. ne the SAR of the piperazinyl-glutamate-pyridines for more potent analogs with improved pharmacokinetic profiles are described. Exploring substituted piperidines and other ring systems at the 4-pyridyl position led to compounds with improved potency and pharmacokinetic properties over candidate I. In particular, compounds 4t and 5t were discovered with a 10-fold improvement over potency and improved pharmacokinetic profiles in both the rat and dog. (C) 2010 Elsevier Ltd. All rights reserved.