CVT-12,012 | 1018675-35-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: CVT-12,012
• 英文别名: 2-hydroxy-N-{2-[3-methyl-2-oxo-7-(((3-trifluoromethyl-phenyl)methyl)amino)-2H-quinoxalin-1-yl]-ethyl}-acetamide；2-Hydroxy-N-(2-(3-methyl-2-oxo-7-(((3-(trifluoromethyl)phenyl)methyl)amino)-1,2-dihydroquinoxalin-1-yl)ethyl)acetamide；2-hydroxy-N-[2-[3-methyl-2-oxo-7-[[3-(trifluoromethyl)phenyl]methylamino]quinoxalin-1-yl]ethyl]acetamide
• CAS: 1018675-35-8
• 化学式: C₂₁H₂₁F₃N₄O₃
• 分子量: 434.418
• InChiKey: HRAQDVZJYIAWOV-UHFFFAOYSA-N

物化性质

• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  DMF：30mg/mL； DMSO：30mg/mL； DMSO:PBS (pH 7.2) (1:6)：0.14 mg/ml；乙醇：1mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  94
• 氢给体数：
  3
• 氢受体数：
  8

制备方法与用途

生物活性

CVT-12012 是一种有效的、具有口服活性的硬脂酰-CoA 去饱和酶 (SCD) 抑制剂，对大鼠微粒体和人 HEPG2 的 IC50 值分别为 38 nM 和 6.1 nM。

靶点

IC50: 38 nM (大鼠微粒体)，6.1 nM (人类 HEPG2)。

体外研究

CVT-12012（化合物 5b）在微粒体和 HEPG2 SCD 活性测定中表现出最高的效力，其 IC50 值分别为 38 nM 和 6.1 nM，优于其他甲基取代的化合物。

体内研究

CVT-12012 在大鼠药代动力学研究中显示出良好的口服生物利用度（78%）。根据 Caco-2 测定结果，CVT-12012 的口服吸收未受显著 Pgp 排泄的影响。其血浆清除率较高，为 88 mL/min/kg，消除半衰期约为 1 小时。

反应信息

• 作为产物：
  描述：

  {2-[3-methyl-2-oxo-7-(3-trifluoromethyl-benzylamino)-2H-quinoxalin-1-yl]-ethylcarbamoyl}-methyl acetate 在 甲醇 、 lithium hydrochloride monohydrate 、 水 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 生成 CVT-12,012
  参考文献：
  名称：

  Potent, orally bioavailable, liver-selective stearoyl-CoA desaturase (SCD) inhibitors

  摘要：

  Two structurally distinct series of SCD (Delta 9 desaturase) inhibitors (1 and 2) have been previously reported by our group. In the present work, we merged the structural features of the two series. This led to the discovery of compound 5b (CVT-12,012) which is highly potent in a human cell-based (HEPG2) SCD assay (IC(50) = 6 nM). This compound has 78% oral bioavailability in rats and is preferentially distributed into liver (76 times vs plasma) with relatively low brain penetration. In a five-day study (sucrose fed rats) compound 5b significantly reduced SCD activity in a dose-dependent manner as determined by GC analysis of fatty acid composition in plasma and liver, and significantly reduced liver triglycerides versus the control group (similar to 50%). (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2009.06.017

文献信息

• [EN] BICYCLIC NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS FOR USE AS STEAROYL COA DESATURASE INHIBITORS<br/>[FR] COMPOSÉS HÉTÉROCYCLIQUES BICYCLIQUES CONTENANT DE L'AZOTE POUR UNE UTILISATION EN TANT QU'INHIBITEURS DE LA STÉAROYL-COA DÉSATURASE
  申请人：CV THERAPEUTICS INC

  公开号：WO2009126123A1

  公开（公告）日：2009-10-15

  The present invention discloses bicyclic nitrogen-containing heterocyclic compounds for use as inhibitors of stearoyl-CoA desaturase. The compounds are useful in treating and/or preventing various human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to abnormal lipid levels, cardiovascular disease, diabetes, obesity, oily skin conditions, metabolic syndrome, and the like.

  本发明揭示了用作硬脂酰辅酶A去饱和酶抑制剂的双环氮杂环化合物。这些化合物在治疗和/或预防由硬脂酰辅酶A去饱和酶（SCD）酶介导的各种人类疾病方面非常有用，特别是与异常脂质水平、心血管疾病、糖尿病、肥胖、油性皮肤状况、代谢综合征等相关的疾病。
• Bicyclic Nitrogen-containing Heterocyclic compounds for use as Stearoyl CoA Desaturase inhibitors
  申请人：Koltun Dmitry

  公开号：US20080255130A1

  公开（公告）日：2008-10-16

  The present invention discloses bicyclic nitrogen-containing heterocyclic compounds for use as inhibitors of stearoyl-CoA desaturase. The compounds are useful in treating and/or preventing various human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to abnormal lipid levels, cardiovascular disease, diabetes, obesity, oily skin conditions, metabolic syndrome, and the like.

  本发明揭示了用作硬脂酰辅酶A去饱和酶抑制剂的双环氮杂环化合物。这些化合物在治疗和/或预防由硬脂酰辅酶A去饱和酶（SCD）酶介导的各种人类疾病方面非常有用，特别是与异常脂质水平、心血管疾病、糖尿病、肥胖、油性皮肤状况、代谢综合征等相关的疾病。
• BICYCLIC NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS FOR USE AS STEAROYL CoA DESATURASE INHIBITORS
  申请人：Chisholm Jeffrey

  公开号：US20080139570A1

  公开（公告）日：2008-06-12

  The present invention discloses bicyclic nitrogen-containing heterocyclic compounds for use as inhibitors of stearoyl-CoA desaturase. The compounds are useful in treating and/or preventing various human diseases, mediated by stearoyl-CoA desaturase (SCD) enzymes, especially diseases related to abnormal lipid levels, cardiovascular disease, diabetes, obesity, oily skin conditions, metabolic syndrome, and the like.

  本发明揭示了双环氮杂环化合物，用作硬脂酰辅酶A去饱和酶的抑制剂。这些化合物在治疗和/或预防各种由硬脂酰辅酶A去饱和酶（SCD）酶介导的人类疾病中很有用，尤其是与异常脂质水平、心血管疾病、糖尿病、肥胖、油性皮肤状况、代谢综合征等相关的疾病。
• BICYCLIC NITROGEN-CONTAINING HETEROCYCLIC COMPOUNDS FOR USE AS STEAROYL COA DESATURASE INHIBITORS
  申请人：CV THERAPEUTICS, INC.

  公开号：EP2066665A2

  公开（公告）日：2009-06-10
• BICYCLIC NITROGEN CONTAINING HETEROCYCLIC COMPOUNDS FOR USE AS STEAROYL COA DESATURASE INHIBITORS
  申请人：Gilead Sciences, Inc.

  公开号：EP2276748A1

  公开（公告）日：2011-01-26