MDF2085

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: MDF2085
• 英文别名: methyl (2R,3R,6R)-4-benzoyl-9-[(2,3-difluoro-4-methylphenyl)methyl]-10-(dimethylcarbamoyl)-3-[(4-fluorophenyl)methyl]-4,9-diazatricyclo[6.3.0.02,6]undeca-1(8),10-diene-3-carboxylate
• 化学式: C₃₆H₃₄F₃N₃O₄
• 分子量: 629.679
• InChiKey: LCNZCPVCFOQWCP-IQVNUPNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  46
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  71.8
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-o-Methylfluorescein phosphate 、 MDF2085 在 human mitogen-activated protein kinase phosphatase-1 作用下， 反应 1.0h， 生成 3-O-methylfluorescein
  参考文献：
  名称：

  Structurally Unique Inhibitors of Human Mitogen-Activated Protein Kinase Phosphatase-1 Identified in a Pyrrole Carboxamide Library

  摘要：

  丝裂原活化蛋白激酶磷酸酶1（MKP-1）是一种酪氨酸磷酸酶超家族成员，能够去磷酸化并灭活重要的丝裂原活化蛋白激酶（MAPK）底物，如p38、c-Jun NH2末端激酶和细胞外信号调节激酶。尽管这些MAPK底物调控与人类疾病相关的许多基本细胞过程，但描述的药理学抑制剂寥寥无几。目前缺乏可获得的选择性MKP-1抑制剂严重限制了对MKP-1生物学角色的研究，这也是我们采用最近描述的三环吡咯-2-羧酰胺库进行筛选的一个理由。在本报告中，我们通过发现172个成员中有10个抑制了人类MKP-1，展示了吡咯羧酰胺库的药理学丰富性。其中两种吡咯羧酰胺，PSI2106和MDF2085，是重组人类MKP-1酶活性的显著体外抑制剂，IC50值分别为8.0 ± 0.9和8.3 ± 0.8 μM。两者对MKP-1的选择性优于密切相关的磷酸酶MKP-3、Cdc25B、VHR和PTP1B。计算分析催化位点附近的表面性质发现，所研究的磷酸酶在底物结合位点的静电势上存在显著差异。化合物对MKP-1的抑制是可逆的，但表现出混合动力学。在生理相关浓度的谷胱甘肽存在下，磷酸酶抑制得以保持。分子对接研究提示PSI2106可能与MKP-1上的His229和Phe299相互作用。这些结果显示了使用小型聚焦库识别药理学探针的效力。

  DOI：

  10.1124/jpet.107.122242

文献信息

• Structurally Unique Inhibitors of Human Mitogen-Activated Protein Kinase Phosphatase-1 Identified in a Pyrrole Carboxamide Library
  作者：John S. Lazo、John J. Skoko、Stefan Werner、Branko Mitasev、Ahmet Bakan、Fumito Koizumi、Archibong Yellow-Duke、Ivet Bahar、Kay M. Brummond

  DOI：10.1124/jpet.107.122242

  日期：2007.9

  Mitogen-activated protein kinase phosphatase 1 (MKP-1) is a tyrosine phosphatase superfamily member that dephosphorylates and inactivates cardinal mitogen-activated protein kinase (MAPK) substrates, such as p38, c-Jun NH2-terminal kinase, and extracellular signal-regulated kinase. Although these MAPK substrates regulate many essential cellular processes associated with human diseases, few pharmacological inhibitors have been described. The lack of readily available selective MKP-1 inhibitors has severely limited interrogation of its biological role and was one rationale for using a recently described tricyclic pyrrole-2-carboxamide library in our screening efforts. In this report we demonstrate the pharmacological richness of the pyrrole carboxamide library by the finding that 10 of 172 members inhibited human MKP-1. Two of the pyrrole carboxamides, PSI2106 and MDF2085, were especially notable in vitro inhibitors of recombinant human MKP-1 enzyme activity with IC50 values of 8.0 ± 0.9 and 8.3 ± 0.8 μM, respectively. Both showed some selectivity for MKP-1 over the closely related phosphatases MKP-3, Cdc25B, VHR, and PTP1B. Computational examination of the surface properties near the catalytic site revealed that the phosphatases studied differ significantly in their electrostatic potential at the substrate binding site. The compounds inhibited MKP-1 reversibly but displayed mixed kinetics. Phosphatase inhibition was retained in the presence of physiologically relevant concentrations of glutathione. Molecular docking studies suggested that PSI2106 may interact with His229 and Phe299 on MKP-1. These results reveal the power of using a small focused library for identifying pharmacological probes.

  丝裂原活化蛋白激酶磷酸酶1（MKP-1）是一种酪氨酸磷酸酶超家族成员，能够去磷酸化并灭活重要的丝裂原活化蛋白激酶（MAPK）底物，如p38、c-Jun NH2末端激酶和细胞外信号调节激酶。尽管这些MAPK底物调控与人类疾病相关的许多基本细胞过程，但描述的药理学抑制剂寥寥无几。目前缺乏可获得的选择性MKP-1抑制剂严重限制了对MKP-1生物学角色的研究，这也是我们采用最近描述的三环吡咯-2-羧酰胺库进行筛选的一个理由。在本报告中，我们通过发现172个成员中有10个抑制了人类MKP-1，展示了吡咯羧酰胺库的药理学丰富性。其中两种吡咯羧酰胺，PSI2106和MDF2085，是重组人类MKP-1酶活性的显著体外抑制剂，IC50值分别为8.0 ± 0.9和8.3 ± 0.8 μM。两者对MKP-1的选择性优于密切相关的磷酸酶MKP-3、Cdc25B、VHR和PTP1B。计算分析催化位点附近的表面性质发现，所研究的磷酸酶在底物结合位点的静电势上存在显著差异。化合物对MKP-1的抑制是可逆的，但表现出混合动力学。在生理相关浓度的谷胱甘肽存在下，磷酸酶抑制得以保持。分子对接研究提示PSI2106可能与MKP-1上的His229和Phe299相互作用。这些结果显示了使用小型聚焦库识别药理学探针的效力。