(2R)-5,5-dimethyl-1-(2-cyclohexyl-1,2-dioxoethyl)-2-(4-thiazolidine)carboxylic acid | 533933-50-5

• 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: (2R)-5,5-dimethyl-1-(2-cyclohexyl-1,2-dioxoethyl)-2-(4-thiazolidine)carboxylic acid
• 英文别名: (4R)-3-(2-cyclohexyl-2-oxoacetyl)-2,2-dimethyl-1,3-thiazolidine-4-carboxylic acid
• CAS: 533933-50-5
• 化学式: C₁₄H₂₁NO₄S
• 分子量: 299.391
• InChiKey: VRXPBGBDRKNRDB-JTQLQIEISA-N

物化性质

• 沸点：
  475.8±55.0 °C(Predicted)
• 密度：
  1.261±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  100
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R)-5,5-dimethyl-1-(2-cyclohexyl-1,2-dioxoethyl)-2-(4-thiazolidine)carboxylic acid 、 3-苯丙醇 在 4-二甲氨基吡啶 、 camphor-10-sulfonic acid 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以71.2%的产率得到3-phenyl-1-propyl(2R)-5,5-dimethyl-1-(2-cyclohexyl-1,2-dioxoethyl)-2-(4-thiazolidine)carboxylate
  参考文献：
  名称：

  FK506-Binding Protein Ligands:  Structure-Based Design, Synthesis, and Neurotrophic/Neuroprotective Properties of Substituted 5,5-Dimethyl-2-(4-thiazolidine)carboxylates

  摘要：

  Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)- 5,5-dimethyl- 1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine) carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.

  DOI：

  10.1021/jm0502384
• 作为产物：
  描述：

  环己氯化镁 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 为溶剂， 反应 5.0h， 生成 (2R)-5,5-dimethyl-1-(2-cyclohexyl-1,2-dioxoethyl)-2-(4-thiazolidine)carboxylic acid
  参考文献：
  名称：

  FK506-Binding Protein Ligands:  Structure-Based Design, Synthesis, and Neurotrophic/Neuroprotective Properties of Substituted 5,5-Dimethyl-2-(4-thiazolidine)carboxylates

  摘要：

  Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)- 5,5-dimethyl- 1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine) carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.

  DOI：

  10.1021/jm0502384

文献信息

• Substituted 5-membered n-heterocyclic compounds and their uses for treating or preventing neurodegenerative diseases
  申请人：Li Song

  公开号：US20050171166A1

  公开（公告）日：2005-08-04

  This invention relates to substituted 5-membered N-Herterocyclic neurotrophic compounds of formula (I) or pharmaceutically acceptable salts or hydrates thereof, wherein R 1 , R 2 , R 3 , R 4 , V, W, X, Y, and Z are as defined in the description; their preparation methods, compositions comprising the same, and their use as inhibitors of FK560 binding proteases (FKBPs) activity for treating and preventing neurodegenerative diseases and other nerve disorders associated with nerve injuries or other related diseases.

  本发明涉及式(I)的取代5-成员N-杂环神经营养化合物或其药学上可接受的盐或水合物，其中R1、R2、R3、R4、V、W、X、Y和Z如描述中定义；它们的制备方法、包含它们的组合物，以及它们作为FK560结合蛋白酶（FKBPs）活性的抑制剂用于治疗和预防神经退行性疾病和与神经损伤或其他相关疾病相关的其他神经紊乱。
• FK506-Binding Protein Ligands:  Structure-Based Design, Synthesis, and Neurotrophic/Neuroprotective Properties of Substituted 5,5-Dimethyl-2-(4-thiazolidine)carboxylates
  作者：Liqin Zhao、Wei Huang、Hongying Liu、Lili Wang、Wu Zhong、Junhai Xiao、Yuandong Hu、Song Li

  DOI：10.1021/jm0502384

  日期：2006.7.1

  Structure-based design and discovery of novel neuroimmunophilin FK506-binding protein (FKBP) ligands were pursued in the present study. The binding mode of the known FKBP ligand 1 (3-(3-pyridyl)-1-propyl (2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate) in complex with FKBP12 was investigated using LUDI simulation and upon which a novel scaffold structure predicted to possess improved binding affinity was designed. A virtual combinatorial library composed of diverse combinations of two substituted groups was constructed using Project Library, followed by an automated screening of the library against the ligand binding site on FKBP52 using DOCK. Forty-three candidate compounds that displayed favorable binding with the receptor were identified and synthesized. The neurotrophic activity of the candidate compounds was evaluated on chick dorsal root ganglion cultures in vitro. As a result, 15 compounds exhibited positive effects on ganglion neurite outgrowth in the presence of 0.15 ng/mL NGF, among which 7 compounds at testing concentrations of 1 pM and 100 pM showed greater efficacy than 1 at 100 pM. Compound 18 (3-(3-pyridyl)-1-propyl (2S)- 5,5-dimethyl- 1-(3,3-dimethyl-1,2-dioxobutyl)-2-(4-thiazolidine) carboxylate) afforded the most potent effect in promoting the processes of neurite outgrowth and which was in a concentration-dependent manner from 1 pM to 100 pM. Half-maximal effect occurred at about 10 pM. Moreover, 18 at a dosage of 10 mg/kg was found to be significantly neuroprotective in a mouse peripheral sympathetic nerve injury model induced by 8 mg/kg 6-hydroxydopamine. This study further suggests the clinical potential of novel FKBP ligands as a new therapeutic approach in the treatment of neurodegenerative disorders, such as Parkinson's disease.