(S)-1,1,1-trifluoro-2-(piperidin-4-yl)propan-2-ol | 1558709-96-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: (S)-1,1,1-trifluoro-2-(piperidin-4-yl)propan-2-ol
• 英文别名: (2S)-1,1,1-trifluoro-2-piperidin-4-ylpropan-2-ol
• CAS: 1558709-96-8
• 化学式: C₈H₁₄F₃NO
• 分子量: 197.2
• InChiKey: CLMDMJJVIPEREU-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  32.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1H-benzo[d]imidazol-2-yl)(4-((3-chloropyrazin-2-yl)oxy)phenyl)methanone 、 (S)-1,1,1-trifluoro-2-(piperidin-4-yl)propan-2-ol 以 二甲基亚砜 为溶剂， 以11.7%的产率得到(S)-(1H-benzo[d]imidazol-2-yl)(4-(3-(4-(1,1,1-trifluoro-2-hydroxypropan-2-yl)piperidin-1-yl)pyrazin-2-yloxy)phenyl)methanone
  参考文献：
  名称：

  Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)

  摘要：

  Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.

  DOI：

  10.1021/jm401234w

文献信息

• [EN] PYRAZOLO[1,5a]PYRIMIDINE DERIVATIVES AS IRAK4 MODULATORS<br/>[FR] DÉRIVÉS PYRAZOLO [1,5 A]PYRIMIDINE EN TANT QUE MODULATEURS D'IRAK 4
  申请人：HOFFMANN LA ROCHE

  公开号：WO2017108723A2

  公开（公告）日：2017-06-29

  Compounds of Formula (0), Formula (I), and Formula (II) and methods of use as Interleukin-1 Receptor Associated Kinase (IRAK4) inhibitors are described herein.
• Design, Optimization, and Biological Evaluation of Novel Keto-Benzimidazoles as Potent and Selective Inhibitors of Phosphodiesterase 10A (PDE10A)
  作者：Essa Hu、Roxanne K. Kunz、Ning Chen、Shannon Rumfelt、Aaron Siegmund、Kristin Andrews、Samer Chmait、Sharon Zhao、Carl Davis、Hang Chen、Dianna Lester-Zeiner、Ji Ma、Christopher Biorn、Jianxia Shi、Amy Porter、James Treanor、Jennifer R. Allen

  DOI：10.1021/jm401234w

  日期：2013.11.14

  Our development of PDE10A inhibitors began with an HTS screening hit (1) that exhibited both high p-glycoprotein (P-gp) efflux ratios in rat and human and poor metabolic stability. On the basis of cocrystal structure of 1 in human PDE10A enzyme, we designed a novel keto-benzimidazole 26 with comparable PDE10A potency devoid of efflux liabilities. On target in vivo coverage of PDE10A in rat brain was assessed using our previously reported LC-MS/MS receptor occupancy (RO) technology. Compound 26 achieved 55% RO of PDE10A at 30 mg/kg po and covered PDE10A receptors in rat brain in a dose-dependent manner. Cocrystal structure of 26 in PDE10A confirmed the binding mode of the novel scaffold. Further optimization resulted in the identification of keto-benzimidazole 34, which showed an increased in vivo efficacy of 57% RO in rats at 10 mg/kg po and an improved in vivo rat clearance and oral bioavailability.