2-{4-[5-(4-chloro-3-trifluoromethylphenyl)-[1,3,4]oxadiazol-2-yl]-butyl}-[1,8]naphthyridine | 1314796-67-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2-{4-[5-(4-chloro-3-trifluoromethylphenyl)-[1,3,4]oxadiazol-2-yl]-butyl}-[1,8]naphthyridine
• 英文别名: 2-[4-Chloro-3-(trifluoromethyl)phenyl]-5-[4-(1,8-naphthyridin-2-yl)butyl]-1,3,4-oxadiazole；2-[4-chloro-3-(trifluoromethyl)phenyl]-5-[4-(1,8-naphthyridin-2-yl)butyl]-1,3,4-oxadiazole
• CAS: 1314796-67-2
• 化学式: C₂₁H₁₆ClF₃N₄O
• 分子量: 432.832
• InChiKey: IEIRGUKKLCLATB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  64.7
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  乙基6-氧代庚酸酯 在 lithium hydroxide monohydrate 、 水 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 1,2-二氯乙烷 、 L-脯氨酸 、 三氯氧磷 作用下， 以 四氢呋喃 、 N-甲基吡咯烷酮 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 57.0h， 生成 2-{4-[5-(4-chloro-3-trifluoromethylphenyl)-[1,3,4]oxadiazol-2-yl]-butyl}-[1,8]naphthyridine
  参考文献：
  名称：

  Discovery of a potent and selective small molecule hGPR91 antagonist

  摘要：

  GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 mu M)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; > 100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; > 100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.04.091

文献信息

• Discovery of a potent and selective small molecule hGPR91 antagonist
  作者：Debnath Bhuniya、Dhananjay Umrani、Bhavesh Dave、Deepak Salunke、Gagan Kukreja、Jayasagar Gundu、Minakshi Naykodi、Nadim S. Shaikh、Prasad Shitole、Santosh Kurhade、Siddhartha De、Sreemita Majumdar、Srinivasa B. Reddy、Suhas Tambe、Yogesh Shejul、Anita Chugh、Venkata P. Palle、Kasim A. Mookhtiar、Doris Cully、Joseph Vacca、Prasun K. Chakravarty、Ravi P. Nargund、Samuel D. Wright、Michael P. Graziano、Sheo B. Singh、Sophie Roy、Tian-Quan Cai

  DOI：10.1016/j.bmcl.2011.04.091

  日期：2011.6

  GPR91, a 7TM G-Protein-Coupled Receptor, has been recently deorphanized with succinic acid as its endogenous ligand. Current literature indicates that GPR91 plays role in various pathophysiology including renal hypertension, autoimmune disease and retinal angiogenesis. Starting from a small molecule high-throughput screening hit 1 (hGPR91 IC(50): 0.8 mu M)-originally synthesized in Merck for Bradykinin B(1) Receptor (BK(1)R) program, systematic structure-activity relationship study led us to discover potent and selective hGPR91 antagonists e.g. 2c, 4c, and 5g (IC(50): 7-35 nM; >1000 fold selective against hGPR99, a closest related GPCR; > 100 fold selective in Drug Matrix screening). This initial work also led to identification of two structurally distinct and orally bio-available lead compounds: 5g (%F: 26) and 7e (IC(50): 180 nM; > 100 fold selective against hGPR99; %F: 87). A rat pharmacodynamic assay was developed to characterize the antagonists in vivo using succinate induced increase in blood pressure. Using two representative antagonists, 2c and 4c, the GPR91 target engagement was subsequently demonstrated using the designed pharmacodynamic assay. (C) 2011 Elsevier Ltd. All rights reserved.