3-[2-(4-isopropoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynylamine | 903886-78-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-[2-(4-isopropoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynylamine
• 英文别名: 4-(2-(4-isopropoxyphenoxy)thiazol-5-yl)but-3-yn-2-amine；3-[2-(4-isopropoxy-phenoxy)-thiazol-5-yl]-1-methyl-prop-2-ynylamine；4-[2-(4-propan-2-yloxyphenoxy)-1,3-thiazol-5-yl]but-3-yn-2-amine
• CAS: 903886-78-2
• 化学式: C₁₆H₁₈N₂O₂S
• 分子量: 302.397
• InChiKey: RPPRRVPGJJKVHJ-UHFFFAOYSA-N

物化性质

• 沸点：
  448.2±55.0 °C(Predicted)
• 密度：
  1.22±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  85.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-[2-(4-isopropoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynylamine 生成 2-(4-(2-(4-Isopropoxyphenoxy)thiazol-5-yl)but-3-yn-2-ylamino)-2-oxoacetic acid
  参考文献：
  名称：

  The synthesis and structure–activity relationship studies of selective acetyl-CoA carboxylase inhibitors containing 4-(thiazol-5-yl)but-3-yn-2-amino motif: Polar region modifications

  摘要：

  The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency. (c) 2006 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2006.12.047
• 作为产物：
  描述：

  2-{3-[2-(4-isopropoxyphenoxy)thiazol-5-yl]-1-methyl-prop-2-ynyl}isoindole-1,3-dione 在 一水合肼 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 1.0h， 生成 3-[2-(4-isopropoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynylamine
  参考文献：
  名称：

  N- {3- [2-（4-烷氧基苯氧基）噻唑-5-基] -1-甲基丙-2-炔基}羧基衍生物作为选择性乙酰辅酶A羧化酶2抑制剂的合成与构效关系。

  摘要：

  从高通量筛选中鉴定出一种结构新颖的乙酰辅酶A羧化酶（ACC）抑制剂。初步的结构活性关系研究导致发现了针对人重组ACC1和ACC2的有效双重ACC1 / ACC2和ACC2选择性抑制剂。选择性ACC2抑制剂表现出的IC50 <20 nM和对ACC1的选择性> 1000倍。在急性啮齿动物研究中，（S）-对映异构体9p表现出较高的ACC2活性并降低了肌肉丙二酰辅酶A的剂量依赖性，而（R）-对映异构体9o则较弱，对丙二酰辅酶A的水平没有影响。

  DOI：

  10.1021/jm060484v

文献信息

• Novel acetyl-CoA carboxylase (ACC) inhibitors and their use in diabetes, obesity and metabolic syndrome
  申请人：Beutel A. Bruce

  公开号：US20060178400A1

  公开（公告）日：2006-08-10

  The present invention relates to compounds of formula (I), which inhibit acetyl-CoA carboxylase (ACC) and are useful for the prevention or treatment of metabolic syndrome, type II diabetes, obesity, atherosclerosis and cardiovascular diseases in humans.

  本发明涉及式(I)的化合物，它们抑制乙酰辅酶A羧化酶（ACC），并且对于预防或治疗人类的代谢综合征、2型糖尿病、肥胖、动脉粥样硬化和心血管疾病是有用的。
• <i>N</i>-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1-methylprop-2-ynyl}carboxy Derivatives as Acetyl-CoA Carboxylase InhibitorsImprovement of Cardiovascular and Neurological Liabilities via Structural Modifications
  作者：Yu Gui Gu、Moshe Weitzberg、Richard F. Clark、Xiangdong Xu、Qun Li、Nathan L. Lubbers、Yi Yang、David W. A. Beno、Deborah L. Widomski、Tianyuan Zhang、T. Matthew Hansen、Robert F. Keyes、Jeffrey F. Waring、Sherry L. Carroll、Xiaojun Wang、Rongqi Wang、Christine H. Healan-Greenberg、Eric A. Blomme、Bruce A. Beutel、Hing L. Sham、Heidi S. Camp

  DOI：10.1021/jm070035a

  日期：2007.3.1

  A preliminary safety evaluation of ACC2 inhibitor 1-(S) revealed serious neurological and cardiovascular liabilities of this chemotype. A systematic structure-toxicity relationship study identified the alkyne linker as the key motif responsible for these adverse effects. Toxicogenomic studies in rats showed that 1-(R) and 1-(S) induced gene expression patterns similar to that seen with several known

  ACC2抑制剂1-（S）的初步安全性评估显示，该化学型严重的神经系统和心血管疾病。一项系统的结构-毒性关系研究确定了炔烃连接体为造成这些不利影响的关键基序。在大鼠中进行的毒理基因组研究表明，1-（R）和1-（S）诱导的基因表达模式与几种已知的心脏毒性剂（如阿霉素）相似。用替代的连接基团取代炔烃导致了一系列新的ACC抑制剂，其心血管和神经系统特性得到了显着改善。
• Synthesis and Structure−Activity Relationships of <i>N</i>-{3-[2-(4-Alkoxyphenoxy)thiazol-5-yl]-1- methylprop-2-ynyl}carboxy Derivatives as Selective Acetyl-CoA Carboxylase 2 Inhibitors
  作者：Yu Gui Gu、Moshe Weitzberg、Richard F. Clark、Xiangdong Xu、Qun Li、Tianyuan Zhang、T. Matthew Hansen、Gang Liu、Zhili Xin、Xiaojun Wang、Rongqi Wang、Teresa McNally、Heidi Camp、Bruce A. Beutel、Hing L. Sham

  DOI：10.1021/jm060484v

  日期：2006.6.1

  A structurally novel acetyl-CoA carboxylase (ACC) inhibitor is identified from high-throughput screening. A preliminary structure-activity relationship study led to the discovery of potent dual ACC1/ACC2 and ACC2 selective inhibitors against human recombinant ACC1 and ACC2. Selective ACC2 inhibitors exhibited IC50<20 nM and >1000-fold selectivity against ACC1. (S)-Enantiomer 9p exhibited high ACC2

  从高通量筛选中鉴定出一种结构新颖的乙酰辅酶A羧化酶（ACC）抑制剂。初步的结构活性关系研究导致发现了针对人重组ACC1和ACC2的有效双重ACC1 / ACC2和ACC2选择性抑制剂。选择性ACC2抑制剂表现出的IC50 <20 nM和对ACC1的选择性> 1000倍。在急性啮齿动物研究中，（S）-对映异构体9p表现出较高的ACC2活性并降低了肌肉丙二酰辅酶A的剂量依赖性，而（R）-对映异构体9o则较弱，对丙二酰辅酶A的水平没有影响。
• The synthesis and structure–activity relationship studies of selective acetyl-CoA carboxylase inhibitors containing 4-(thiazol-5-yl)but-3-yn-2-amino motif: Polar region modifications
  作者：Xiangdong Xu、Moshe Weitzberg、Robert F. Keyes、Qun Li、Rongqi Wang、Xiaojun Wang、Xiaolin Zhang、Ernst U. Frevert、Heidi S. Camp、Bruce A. Beutel、Hing L. Sham、Yu Gui Gu

  DOI：10.1016/j.bmcl.2006.12.047

  日期：2007.3

  The structure-activity relationship study focused on the polar region of the HTS hit A-80040 (1) producing several series of potent and selective ACC2 inhibitors. The SAR suggests a compact lipophilic pocket that does not tolerate polar and ionic groups. Replacement of the hydroxyurea group with isoxazoles improves ACC2 selectivity while maintaining potency. Variations at the propargylic site of 11a reduce ACC2 potency. (c) 2006 Elsevier Ltd. All rights reserved.