CLH306a

• 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: CLH306a
• 英文别名: 4-(3,5-Ditert-butyl-4-hydroxyphenyl)-2-oxobutanoic acid；4-(3,5-ditert-butyl-4-hydroxyphenyl)-2-oxobutanoic acid
• 化学式: C₁₈H₂₆O₄
• 分子量: 306.402
• InChiKey: ITKLPYXINNJSEE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  74.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  CLH306a 、 二甘醇胺 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 反应 12.0h， 以51%的产率得到4-(3,5-ditert-butyl-4-hydroxyphenyl)-N-[2-(2-hydroxyethoxy)ethyl]-2-oxobutanamide
  参考文献：
  名称：

  A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits

  摘要：

  An gamma-aminobutyric acid type B (GABA(B))-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABA(B)-receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABA(B)-receptor, such as antagonists, show anti-absence seizure activity and procognitive properties. In a search for allosteric compounds of the GABA(B)-receptor, although several positive allosteric modulators have been developed, it is only recently that the first negative allosteric modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABA(B)-receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABA(B)-receptor is a mandatory heterodimer made of GB1 subunits, in which agonists bind, and GB2 subunits, which activate G-proteins. By using various combinations made up of wild-type and/or mutated GB1 and GB2 subunits, we show that CLH304a acts on the heptahelical domain of GB2 subunits. These data revealed the possibility of designing innovative NAMs acting in the heptahelical domain of the GB2 subunits, offering novel possibilities for therapeutic intervention based on GABA(B)-receptor inhibition.

  DOI：

  10.1042/bj20150979
• 作为产物：
  描述：

  3,5-二叔丁基-4-羟基苯甲醛 在 5%-palladium/activated carbon 、 三氟化硼乙醚 、 氢气 、 potassium carbonate 、 氯化铵 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 12.67h， 生成 CLH306a
  参考文献：
  名称：

  Discovery of a Negative Allosteric Modulator of GABA_B Receptors

  摘要：

  Initialized from the scaffold of CGP7930, an allosteric agonist of GABA(B) receptors, a series of non-competitive antagonists were discovered. Among these compounds, compounds 3, 6, and 14 decreased agonist GABA-induced maximal effect of IP3 production in HEK293 cells overexpressing GABA(B) receptors and Gq(j9) proteins without changing the EC50. Compounds 3, 6, and 14 not only inhibited agonist baclofen-induced ERK1/2 phosphorylation but also blocked CGP7930-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABA(B) receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABA(B) receptors. The representative compound 14 decreased GABA-induced IP3 production with IC50 of 37.9 mu M and had no effect on other GPCR Class C members such as mGluR1, mGluR2, and mGluRS. Finally, we showed that compound 14 did not bind to the orthosteric binding sites of GABA(B) receptors, demonstrating that compound 14 negatively modulated GABA(B) receptors activity as a negative allosteric modulator.

  DOI：

  10.1021/ml500162z

文献信息

• US5280045A
  申请人：——

  公开号：US5280045A

  公开（公告）日：1994-01-18
• [EN] DI-TERT-BUTYLPHENOL COMPOUNDS USEFUL AS ANTI-INFLAMMATORY AGENTS
  申请人：THE PROCTER & GAMBLE COMPANY

  公开号：WO1993007865A1

  公开（公告）日：1993-04-29

  (EN) The subject invention involves compositions comprising 4-(3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl)-4-oxobutanamide, or 4-(3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl)-4-oxobutanoic acid and pharmaceutically-acceptable salts thereof, and a pharmaceutically-acceptable carrier. The subject invention also involves methods for treating diseases characterized by inflammation and/or pain, such as rheumatoid arthritis and osteoarthritis, in humans or lower animals by administration of a safe and effective amount of this compound to the human or lower animal in need of such treatment.(FR) Compositions comprenant un 4-(3,5-bis(1,1-diméthyléthyle)-4-hydroxyphényle)-4-oxobutanamide, ou un acide 4-(3,5-bis-(1,1-diméthyléthyle)-4-hydroxyphényle)-4-oxobutanoïque ainsi que des sels pharmaceutiquement acceptables de ceux-ci, et un excipient pharmaceutiquement acceptable. L'invention concerne également des procédés de traitement de maladies caractérisées par une inflammation et/ou des douleurs, telles que la polyarthrite rhumatoïde et l'arthrose, chez l'homme ainsi que chez des animaux inférieurs, par administration d'une dose sans danger et efficace de ce composé à l'homme ou à l'animal inférieur nécessitant un tel traitement.
• A negative allosteric modulator modulates GABAB-receptor signalling through GB2 subunits
  作者：B. Sun、L. Chen、L. Liu、Z. Xia、J.-P. Pin、F. Nan、J. Liu

  DOI：10.1042/bj20150979

  日期：2016.3.15

  An gamma-aminobutyric acid type B (GABA(B))-receptor mediates slow and prolonged synaptic inhibition in the central nervous system, which represents an interesting target for the treatment of various diseases and disorders of the central nervous system. To date, only one activator of the GABA(B)-receptor, baclofen, is on the market for the treatment of spasticity. Inhibitors of the GABA(B)-receptor, such as antagonists, show anti-absence seizure activity and procognitive properties. In a search for allosteric compounds of the GABA(B)-receptor, although several positive allosteric modulators have been developed, it is only recently that the first negative allosteric modulator (NAM), CLH304a (also named Compound 14), has been reported. In the present study, we provide further information on the mechanism of action of CLH304a, and also show the possibility of designing more NAMs, such as CLH391 and CLH393, based on the structure of CLH304a. First we show that CLH304a inhibits native GABA(B)-receptor activity in cultured cerebellar granular neurons. We then show that CLH304a has inverse agonist properties and non-competitively inhibits the effect of agonists, indicating that it binds at a different site to GABA. The GABA(B)-receptor is a mandatory heterodimer made of GB1 subunits, in which agonists bind, and GB2 subunits, which activate G-proteins. By using various combinations made up of wild-type and/or mutated GB1 and GB2 subunits, we show that CLH304a acts on the heptahelical domain of GB2 subunits. These data revealed the possibility of designing innovative NAMs acting in the heptahelical domain of the GB2 subunits, offering novel possibilities for therapeutic intervention based on GABA(B)-receptor inhibition.
• Discovery of a Negative Allosteric Modulator of GABA_B Receptors
  作者：Lin-Hai Chen、Bing Sun、Yang Zhang、Tong-Jie Xu、Zhi-Xiong Xia、Jian-Feng Liu、Fa-Jun Nan

  DOI：10.1021/ml500162z

  日期：2014.7.10

  Initialized from the scaffold of CGP7930, an allosteric agonist of GABA(B) receptors, a series of non-competitive antagonists were discovered. Among these compounds, compounds 3, 6, and 14 decreased agonist GABA-induced maximal effect of IP3 production in HEK293 cells overexpressing GABA(B) receptors and Gq(j9) proteins without changing the EC50. Compounds 3, 6, and 14 not only inhibited agonist baclofen-induced ERK1/2 phosphorylation but also blocked CGP7930-induced ERK1/2 phosphorylation in HEK293 cells overexpressing GABA(B) receptors. The results suggested that compounds 3, 6, and 14 are negative allosteric modulators of GABA(B) receptors. The representative compound 14 decreased GABA-induced IP3 production with IC50 of 37.9 mu M and had no effect on other GPCR Class C members such as mGluR1, mGluR2, and mGluRS. Finally, we showed that compound 14 did not bind to the orthosteric binding sites of GABA(B) receptors, demonstrating that compound 14 negatively modulated GABA(B) receptors activity as a negative allosteric modulator.