N-[(1R)-2-[(5-chloro-6-methyl-2-pyridin-2-ylpyrimidin-4-yl)amino]-1-phenylethyl]-4-[4-(2-hydroxyethyl)piperazin-1-yl]butanamide | 1155269-13-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: N-[(1R)-2-[(5-chloro-6-methyl-2-pyridin-2-ylpyrimidin-4-yl)amino]-1-phenylethyl]-4-[4-(2-hydroxyethyl)piperazin-1-yl]butanamide
• CAS: 1155269-13-8
• 化学式: C₂₈H₃₆ClN₇O₂
• 分子量: 538.093
• InChiKey: QACWKSJESHQSRJ-DEOSSOPVSA-N

物化性质

• 沸点：
  709.2±60.0 °C(predicted)
• 密度：
  1.246±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  38
• 可旋转键数：
  12
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  107
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  4,5-二氯-6-甲基-2-(2-吡啶基)嘧啶 在 四丁基氟化铵 、 sodium carbonate 、 三乙胺 、 三氟乙酸 、 sodium iodide 作用下， 以 四氢呋喃 、 乙二醇二甲醚 为溶剂， 反应 31.5h， 生成 N-[(1R)-2-[(5-chloro-6-methyl-2-pyridin-2-ylpyrimidin-4-yl)amino]-1-phenylethyl]-4-[4-(2-hydroxyethyl)piperazin-1-yl]butanamide
  参考文献：
  名称：

  Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1

  摘要：

  Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure-activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58 analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5'-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a-30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.02.023

文献信息

• INHIBITORS OF HUMAN METHIONINE AMINOPEPTIDASE 1 AND METHODS OF TREATING DISORDERS
  申请人：Liu Jun O.

  公开号：US20110124649A1

  公开（公告）日：2011-05-26

  Described herein are novel pyrimidine-pyridine compounds, methods of inhibiting methionine aminopeptidase and treating disorders (or symptoms thereof) associated with methionine aminopeptidase, wherein a compound of the invention is administered to a subject.
• Pyridinylpyrimidines selectively inhibit human methionine aminopeptidase-1
  作者：Pengtao Zhang、Xinye Yang、Feiran Zhang、Sandra B. Gabelli、Renxiao Wang、Yihua Zhang、Shridhar Bhat、Xiaochun Chen、Manuel Furlani、L. Mario Amzel、Jun O. Liu、Dawei Ma

  DOI：10.1016/j.bmc.2013.02.023

  日期：2013.5

  Cellular protein synthesis is initiated with methionine in eukaryotes with few exceptions. Methionine aminopeptidases (MetAPs) which catalyze the process of N-terminal methionine excision are essential for all organisms. In mammals, type 2 MetAP (MetAP2) is known to be important for angiogenesis, while type 1 MetAP (MetAP1) has been shown to play a pivotal role in cell proliferation. Our previous high-throughput screening of a commercial compound library uncovered a novel class of inhibitors for both human MetAP1 (HsMetAP1) and human MetAP2 (HsMetAP2). This class of inhibitors contains a pyridinylpyrimidine core. To understand the structure-activity relationship (SAR) and to search for analogues of 2 with greater potency and higher HsMetAP1-selectivity, a total of 58 analogues were acquired through either commercial source or by in-house synthesis and their inhibitory activities against HsMetAP1 and HsMetAP2 were determined. Through this systematic medicinal chemistry analysis, we have identified (1) 5-chloro-6-methyl-2-pyridin-2-ylpyrimidine as the minimum element for the inhibition of HsMetAP1; (2) 5'-chloro as the favored substituent on the pyridine ring for the enhanced potency against HsMetAP1; and (3) long C4 side chains as the essentials for higher HsMetAP1-selectivity. At the end of our SAR campaign, 25b, 25c, 26d and 30a-30c are among the most selective and potent inhibitors of purified HsMetAP1 reported to date. In addition, we also performed crystallographic analysis of one representative inhibitor (26d) in complex with N-terminally truncated HsMetAP1. (C) 2013 Elsevier Ltd. All rights reserved.