2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(4-哌啶基)-3-吡啶甲腈盐酸盐 | 406209-26-5

• 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 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 2-氨基-6-[2-(环丙基甲氧基)-6-羟基苯基]-4-(4-哌啶基)-3-吡啶甲腈盐酸盐
• 英文名称: IKK-2 Inhibitor VIII
• 英文别名: 2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-4-piperidin-4-ylpyridine-3-carbonitrile;hydrochloride
• CAS: 406209-26-5
• 化学式: C21H25ClN4O2
• 分子量: 400.9
• InChiKey: QVYAMWAKDKEKMM-UHFFFAOYSA-N

物化性质

• 溶解度：
  DMSO：50 mg/mL（124.72 mM；需要超声波）

计算性质

• 辛醇/水分配系数(LogP)：
  3.59
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  104
• 氢给体数：
  4
• 氢受体数：
  6

制备方法与用途

生物活性

ACHP Hydrochloride (IKK-2 Inhibitor VIII) 是一种有效，选择性的 IKK-β 抑制剂, IC50 为 8.5 nM。

靶点

IKK-β 8.5 nM (IC 50 )

IKK-α 250 nM (IC 50 )

体外研究

ACHP Hydrochloride (Compound 4j) exhibits potent IKK-β inhibitory (IC ₅₀ : 8.5 nM) and cellular activities (IC ₅₀ =40 nM, in A549 cells). ACHP moderately inhibits IKK-α with an IC ₅₀ of 250 nM but exhibits good selectivity towards other kinases, such as IKK3, Syk and MKK4 (IC ₅₀ >20,000 nM). Moreover, ACHP demonstrates quite potent activity in various cellular assays. ACHP inhibits NF-κB-dependent reporter gene activation in TNFα-activated HEK293 cells and PMA/calcium ionophore-activated Jurkat T cells. ACHP fails to inhibit PMA-induced AP-1 activation in MRC-5 cells and PMA/calcium ionophore induced NF-κB dependent reporter gene transcription in Jurkat cells even at concentrations exceeding 10 μM. ACHP selectively interferes with the NF-κB signaling cascade by inhibition of IKK-β in living cells. ACHP inhibits the growth of these cells in a dose-dependent manner. Tax-active cell lines are more susceptible to ACHP than Tax-inactive cell lines and Jurkat (IC ₅₀ values in Tax-active cell lines, Tax-inactive cell lines or Jurkat are 3.1±1.3 μM, 10.7±1.7 μM and 23.6 μM, respectively), suggesting that the growth of Tax-active cells depends on NF-κB more than Tax-inactive cells.

体内研究

ACHP (Compound 4j) is orally bioavailable in mice and rats and demonstrates significant in vivo activity in anti-inflammatory models (arachidonic acid-induced mouse ear edema model). ACHP has reasonable aqueous solubility (0.12 mg/mL in pH 7.4 isotonic buffer) and excellent Caco-2 permeability (P _app 62.3×10 ^-7 cm/s), and demonstrates orally bioavailability in mice (BA: 16%) and rats (BA: 60%). The favourable bioavailability of ACHP in rats is likely due to its low clearance (0.33 L/h/kg). In an acute inflammation model, ACHP exhibits oral efficacy at 1 mg/kg in a dose-dependent manner.