5-chloro-1'-(4-chlorobenzyl)-1-methyl-5',7'-dihydrospiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(1'H)-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 5-chloro-1'-(4-chlorobenzyl)-1-methyl-5',7'-dihydrospiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(1'H)-dione
• 英文别名: 5'-chloro-1-[(4-chlorophenyl)methyl]-1'-methylspiro[5,7-dihydropyrazolo[3,4-b]pyridine-4,3'-indole]-2',6-dione
• 化学式: C₂₁H₁₆Cl₂N₄O₂
• 分子量: 427.29
• InChiKey: DQUNEBLYBSKGGA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  29
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  67.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  5-chloro-1'-(4-chlorobenzyl)-1-methyl-5',7'-dihydrospiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(1'H)-dione 在 Chiralpak IA (4.6x250mm) 5μ 作用下， 生成 (R)-5-chloro-1'-(4-chlorobenzyl)-1-methyl-5',7'-dihydrospiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(1'H)-dione 、 (4S)-5'-chloro-1-[(4-chlorophenyl)methyl]-1'-methylspiro[5,7-dihydropyrazolo[3,4-b]pyridine-4,3'-indole]-2',6-dione
  参考文献：
  名称：

  Lead Optimization of Spiropyrazolopyridones: A New and Potent Class of Dengue Virus Inhibitors

  摘要：

  Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENY) inhibitor, from a DENV serotype 2 (DENV-2) high throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell based lead optimization of the spiropyrazolopyridones focusing on improving the physico-chemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 X 50 mg/kg (bid) or 3 X 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.

  DOI：

  10.1021/ml500521r
• 作为产物：
  描述：

  ethyl 5-amino-1-(4-chlorobenzyl)-1H-pyrazole-4-carboxylate 在 sodium hydroxide 作用下， 以 乙醇 、 水 、 溶剂黄146 为溶剂， 反应 6.0h， 生成 5-chloro-1'-(4-chlorobenzyl)-1-methyl-5',7'-dihydrospiro[indoline-3,4'-pyrazolo[3,4-b]pyridine]-2,6'(1'H)-dione
  参考文献：
  名称：

  Lead Optimization of Spiropyrazolopyridones: A New and Potent Class of Dengue Virus Inhibitors

  摘要：

  Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENY) inhibitor, from a DENV serotype 2 (DENV-2) high throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell based lead optimization of the spiropyrazolopyridones focusing on improving the physico-chemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 X 50 mg/kg (bid) or 3 X 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.

  DOI：

  10.1021/ml500521r

文献信息

• Lead Optimization of Spiropyrazolopyridones: A New and Potent Class of Dengue Virus Inhibitors
  作者：Bin Zou、Wai Ling Chan、Mei Ding、Seh Yong Leong、Shahul Nilar、Peck Gee Seah、Wei Liu、Ratna Karuna、Francesca Blasco、Andy Yip、Alex Chao、Agatha Susila、Hongping Dong、Qing Yin Wang、Hao Ying Xu、Katherine Chan、Kah Fei Wan、Feng Gu、Thierry T. Diagana、Trixie Wagner、Ina Dix、Pei-Yong Shi、Paul W. Smith

  DOI：10.1021/ml500521r

  日期：2015.3.12

  Spiropyrazolopyridone 1 was identified, as a novel dengue virus (DENY) inhibitor, from a DENV serotype 2 (DENV-2) high throughput phenotypic screen. As a general trend within this chemical class, chiral resolution of the racemate revealed that R enantiomer was significantly more potent than the S. Cell based lead optimization of the spiropyrazolopyridones focusing on improving the physico-chemical properties is described. As a result, an optimal compound 14a, with balanced in vitro potency and pharmacokinetic profile, achieved about 1.9 log viremia reduction at 3 X 50 mg/kg (bid) or 3 X 100 mg/kg (QD) oral doses in the dengue in vivo mouse efficacy model.