5-[(1R)-1-{7-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetyl]-2,7-diazaspiro[3.5]non-2-yl}-2,3-dihydro-1H-inden-5-yl]pyridine-2-carboxamide | 1334783-63-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 茚满类
• 英文名称: 5-[(1R)-1-{7-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetyl]-2,7-diazaspiro[3.5]non-2-yl}-2,3-dihydro-1H-inden-5-yl]pyridine-2-carboxamide
• 英文别名: 5-[(1R)-1-[7-[2-(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetyl]-2,7-diazaspiro[3.5]nonan-2-yl]-2,3-dihydro-1H-inden-5-yl]pyridine-2-carboxamide
• CAS: 1334783-63-9
• 化学式: C₃₀H₃₂N₆O₂S
• 分子量: 540.689
• InChiKey: YXWNHDGDJFGTHE-AREMUKBSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  39
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  125
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  tert-butyl 2-[(R)-5-bromo-2,3-dihydro-1H-inden-1-yl]-2,7-diazaspiro[3.5]nonane-7-carboxylate 在 盐酸 、 (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) dichloride 、 potassium acetate 、 过氧化脲素 、 potassium carbonate 、 三乙胺 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 24.75h， 生成 5-[(1R)-1-{7-[(2-methylimidazo[2,1-b][1,3]thiazol-6-yl)acetyl]-2,7-diazaspiro[3.5]non-2-yl}-2,3-dihydro-1H-inden-5-yl]pyridine-2-carboxamide
  参考文献：
  名称：

  Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate

  摘要：

  The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.

  DOI：

  10.1021/ml400473x

文献信息

• Discovery of PF-5190457, a Potent, Selective, and Orally Bioavailable Ghrelin Receptor Inverse Agonist Clinical Candidate
  作者：Samit K. Bhattacharya、Kim Andrews、Ramsay Beveridge、Kimberly O. Cameron、Chiliu Chen、Matthew Dunn、Dilinie Fernando、Hua Gao、David Hepworth、V. Margaret Jackson、Vishal Khot、Jimmy Kong、Rachel E. Kosa、Kimberly Lapham、Paula M. Loria、Allyn T. Londregan、Kim F. McClure、Suvi T. M. Orr、Jigna Patel、Colin Rose、James Saenz、Ingrid A. Stock、Gregory Storer、Maria VanVolkenburg、Derek Vrieze、Guoqiang Wang、Jun Xiao、Yingxin Zhang

  DOI：10.1021/ml400473x

  日期：2014.5.8

  The identification of potent, highly selective orally bioavailable ghrelin receptor inverse agonists from a spiro-azetidino-piperidine series is described. Examples from this series have promising in vivo pharmacokinetics and increase glucose-stimulated insulin secretion in human whole and dispersed islets. A physicochemistry-based strategy to increase lipophilic efficiency for ghrelin receptor potency and retain low clearance and satisfactory permeability while reducing off-target pharmacology led to the discovery of 16h. Compound 16h has a superior balance of ghrelin receptor pharmacology and off-target selectivity. On the basis of its promising pharmacological and safety profile, 16h was advanced to human clinical trials.