ESI-09 | 263707-16-0

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: ESI-09
• 英文别名: 3-(5-tert-butylisoxazol-3-yl)-2-[(3-chlorophenyl)hydrazono]-3-oxopropionitrile；α-(2-(3-chlorophenyl)hydrazinylidene)-5-(1,1-dimethylethyl)-β-oxo-3-isoxazolepropanenitrile；3-[5-(tert-butyl)isoxazol-3-yl]-2-[2-(3-chlorophenyl)hydrazono]-3-oxopropanenitrile；2-(5-tert-butyl-1,2-oxazol-3-yl)-N-(3-chloroanilino)-2-oxoethanimidoyl cyanide
• CAS: 263707-16-0
• 化学式: C₁₆H₁₅ClN₄O₂
• 分子量: 330.774
• InChiKey: DXEATJQGQHDURZ-UHFFFAOYSA-N

物化性质

• 熔点：
  >175°C (dec.)
• 溶解度：
  在DMSO中的溶解度为20mg/mL，澄清

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  91.3
• 氢给体数：
  1
• 氢受体数：
  6

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

ESI-09是一种特定的cAMP直接激活蛋白（EPAC）抑制剂，对EPAC1和EPAC2的IC50分别为3.2 μM 和1.4 μM ，比PKA高出约100倍的选择性。

体外研究

ESI-09，一种新型非环状核苷酸EPAC拮抗剂，能够特异性阻断细胞内EPAC介导的Rap1活化和Akt磷酸化，以及胰腺β细胞中由EPAC介导的胰岛分泌。另一方面，ESI-09不抑制AsPC1细胞中表皮生长因子（EGF）诱导的Akt磷酸化。在胰腺癌细胞中，ESI-09通过剂量依赖性降低007-AM诱导的细胞粘附而抑制细胞迁移和侵袭。此外，ESI-09显著降低了人脐静脉内皮细胞中的总细菌数，并有效拮抗CPT-cAMP 诱导的Schwann细胞（SC）分化及髓鞘形成。在SC神经元培养基中，ESI-09显著降低了O1阳性及MBP阳性的数量，而不影响神经元或SCs自身的健康。

体内研究

ESI-09 (10 mg/kg/d, i.p.) 通过对EPAC1的药理抑制，保护WT C57BL/6小鼠免受致命的SFG立克次氏体病的损害。

靶点

Target	Value
EPAC2	1.4 μM
EPAC1	3.2 μM

反应信息

• 作为反应物：
  描述：

  ESI-09 在 一水合肼 作用下， 以 乙醇 为溶剂， 反应 6.0h， 以64%的产率得到3-(5-tert-butylisoxazol-3-yl)-4-((3-chlorophenyl)diazenyl)-1H-pyrazol-5-amine
  参考文献：
  名称：

  Structure–Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N′-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists

  摘要：

  Exchange proteins directly activated by cAMP (EPAC) as guanine nucleotide exchange factors mediate the effects of the pivotal second messenger cAMP, thereby regulating a wide variety of intracellular physiological and pathophysiological processes. A series of novel 2-(isoxazol-3yl)-2-oxo-N'-phenyl-acetohydrazonoyl cyanide EPAC antagonists was synthesized and evaluated in an effort to optimize properties of the previously identified high-throughput (HTS) hit 1 (ESI-09). Structure activity relationship (SAR) analysis led to the discovery of several more active EPAC antagonists (e.g., 22 (HJC0726), 35 (NY0123), and 47 (NY0173)) with low micromolar inhibitory activity. These inhibitors may serve as valuable pharmacological probes to facilitate our efforts in elucidating the biological functions of EPAC and developing potential novel therapeutics against human diseases. Our SAR ring as well as the 5-position of the results have also revealed that further modification at the 3-, 4-, and 5-positions of the phenyl isoxazole moiety may allow for the development of more potent EPAC antagonists.

  DOI：

  10.1021/acs.jmedchem.5b00635
• 作为产物：
  描述：

  ethyl 2-hydroxy-5,5-dimethyl-4-oxohex-2-enoate 在 盐酸 、 四丁基氟化铵 、 甲基锂 、 sodium nitrite 作用下， 以 四氢呋喃 、 乙醇 、 水 、 乙腈 为溶剂， 反应 5.58h， 生成 ESI-09
  参考文献：
  名称：

  高效合成 ESI-09，一种新型非环核苷酸 EPAC 拮抗剂

  摘要：

  报道了一种简洁有效的合成方法来生产新型非环核苷酸 EPAC 拮抗剂ESI-09及其新类似物。该合成的主要特点包括温和可靠的异恶唑合成子一锅法，以及氰甲基酮关键中间体的改良一锅法。该合成需要廉价的起始材料和仅三个线性步骤即可完成，总产率为 53%。

  DOI：

  10.1016/j.tetlet.2013.01.024

文献信息

• [EN] MODULATORS OF EXCHANGE PROTEINS DIRECTLY ACTIVATED BY CAMP (EPACS)<br/>[FR] MODULATEURS DE PROTÉINES D'ÉCHANGE DIRECTEMENT ACTIVÉES PAR L'AMPC (EPAC)
  申请人：UNIV TEXAS

  公开号：WO2013119931A1

  公开（公告）日：2013-08-15

  Embodiments of the invention are directed to compounds that inhibit an activity of EP AC proteins and methods of using the same. The inventors have developed a sensitive and robust high throughput screening (HTS) assay for the purpose of identifying EPAC specific inhibitors (Tsalkova et al. (2012) PLOS ONE 7(1 ):e30441).

  该发明的实施例涉及抑制EPAC蛋白活性的化合物以及使用这些化合物的方法。发明人已经开发了一种敏感且稳健的高通量筛选（HTS）测定方法，用于识别EPAC特异性抑制剂（Tsalkova等人（2012年）PLOS ONE 7(1)：e30441）。
• MODULATORS OF EXCHANGE PROTEINS DIRECTLY ACTIVATED BY CAMP (EPACS)
  申请人：The Board of Regents of the University of Texas System

  公开号：US20150110809A1

  公开（公告）日：2015-04-23

  Embodiments of the invention are directed to compounds that inhibit an activity of EP AC proteins and methods of using the same. The inventors have developed a sensitive and robust high throughput screening (HTS) assay for the purpose of identifying EPAC specific inhibitors (Tsalkova et al. (2012) PLOS ONE 7 (1):e30441).

  本发明的实施例涉及抑制EPAC蛋白活性的化合物及其使用方法。发明人开发了一种灵敏且强大的高通量筛选（HTS）检测方法，以识别EPAC特异性抑制剂（Tsalkova等人（2012）PLOS ONE 7（1）：e30441）。
• Structure–Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-<i>N</i>′-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists
  作者：Na Ye、Yingmin Zhu、Haijun Chen、Zhiqing Liu、Fang C. Mei、Christopher Wild、Haiying Chen、Xiaodong Cheng、Jia Zhou

  DOI：10.1021/acs.jmedchem.5b00635

  日期：2015.8.13

  Exchange proteins directly activated by cAMP (EPAC) as guanine nucleotide exchange factors mediate the effects of the pivotal second messenger cAMP, thereby regulating a wide variety of intracellular physiological and pathophysiological processes. A series of novel 2-(isoxazol-3yl)-2-oxo-N'-phenyl-acetohydrazonoyl cyanide EPAC antagonists was synthesized and evaluated in an effort to optimize properties of the previously identified high-throughput (HTS) hit 1 (ESI-09). Structure activity relationship (SAR) analysis led to the discovery of several more active EPAC antagonists (e.g., 22 (HJC0726), 35 (NY0123), and 47 (NY0173)) with low micromolar inhibitory activity. These inhibitors may serve as valuable pharmacological probes to facilitate our efforts in elucidating the biological functions of EPAC and developing potential novel therapeutics against human diseases. Our SAR ring as well as the 5-position of the results have also revealed that further modification at the 3-, 4-, and 5-positions of the phenyl isoxazole moiety may allow for the development of more potent EPAC antagonists.
• Efficient synthesis of ESI-09, a novel non-cyclic nucleotide EPAC antagonist
  作者：Haijun Chen、Chunyong Ding、Christopher Wild、Huiling Liu、Tianzhi Wang、Mark A. White、Xiaodong Cheng、Jia Zhou

  DOI：10.1016/j.tetlet.2013.01.024

  日期：2013.3

  A concise and efficient synthetic approach to producing a novel non-cyclic nucleotide EPAC antagonist ESI-09 and its new analogs is reported. Key features of the synthesis include a mild and reliable one-pot procedure for an isoxazole synthon, as well as a modified one-pot protocol for the cyanomethyl ketone key intermediate. The synthesis requires inexpensive starting materials and only three linear

  报道了一种简洁有效的合成方法来生产新型非环核苷酸 EPAC 拮抗剂ESI-09及其新类似物。该合成的主要特点包括温和可靠的异恶唑合成子一锅法，以及氰甲基酮关键中间体的改良一锅法。该合成需要廉价的起始材料和仅三个线性步骤即可完成，总产率为 53%。