2-((1-(2-chlorophenyl)-4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(4-methoxyphenyl)propanamide | 1351413-55-2

• 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: 2-((1-(2-chlorophenyl)-4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(4-methoxyphenyl)propanamide
• 英文别名: 2-[[1-(2-chlorophenyl)-4-oxo-5H-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-N-(4-methoxyphenyl)propanamide
• CAS: 1351413-55-2
• 化学式: C₂₁H₁₉ClN₆O₃
• 分子量: 438.873
• InChiKey: NGJKWXIPEUHCJA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  110
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  5-氨基-1-(2-氯苯基)-1H-吡唑-4-甲腈 在 五氯化磷 、 双氧水 、 Ammonium hydroxide 、 三乙胺 、 异丙醇 、 potassium hydroxide 、 三氯氧磷 作用下， 反应 6.0h， 生成 2-((1-(2-chlorophenyl)-4-hydroxy-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)-N-(4-methoxyphenyl)propanamide
  参考文献：
  名称：

  Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design

  摘要：

  A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 mu M, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.

  DOI：

  10.1021/jm301189c

文献信息

• N-SUBSTITUTED PYRAZOLO [3,4-D] PYRIMIDINE KETONE COMPOUND, AND PREPARATION PROCESS AND USE THEREOF
  申请人：SUN YAT-SEN UNIVERSITY

  公开号：US20150218168A1

  公开（公告）日：2015-08-06

  Disclosed are an N-substituted pyrazolo[3,4-d]pyrimidine ketone compound of formula (I), and a preparation process and use thereof as a phosphodiesterase IX (PDEIX) inhibitor: wherein R′ is selected from isopropyl, cyclopentyl, cyclohexyl, isobutyl, and o-chlorophenyl; when R″═CH 3 , R represents benzyl; and when R″═H, R is selected from 3-methylpyridine, 1-phenylethyl, 1-(4-chlorophenyl)ethyl, D- or L-configured CHCH 3 CONHR′″, D- or L-configured CH 2 CONHR′″, D- or L-configured CH 2 CH 2 CONHR′″; wherein R 1 is selected from hydrogen, chlorine, methoxy, methyl, trifluoromethyl, dimethoxy, methylenedioxy, and dichlorine, and R 2 is selected from hydrogen, methoxy, ethoxy, isopropoxy, methyl, dimethoxy, and 2-methyl-4-methoxy, and wherein R′″ is p-methoxyphenyl.

  本发明公开了一种式为(I)的N-取代吡唑并[3,4-d]嘧啶酮化合物，以及其作为磷酸二酯酶IX（PDEIX）抑制剂的制备方法和用途： 其中， 当R″ = CH3时，R代表苄基； 当R″ = H时，R选自3-甲基吡啶，1-苯乙基，1-(4-氯苯基)乙基，D-或L-构型的CHCH3CONHR′″，D-或L-构型的CH2CONHR′″，D-或L-构型的CH2CH2CONHR′″； 其中R′选自异丙基，环戊基，环己基，异丁基和o-氯苯基； 其中R1选自氢，氯，甲氧基，甲基，三氟甲基，二甲氧基，甲亚氧基和二氯，R2选自氢，甲氧基，乙氧基，异丙氧基，甲基，二甲氧基和2-甲基-4-甲氧基，其中R′″为对甲氧基苯基。
• US9617269B2
  申请人：——

  公开号：US9617269B2

  公开（公告）日：2017-04-11
• Structure-Based Discovery of Highly Selective Phosphodiesterase-9A Inhibitors and Implications for Inhibitor Design
  作者：Fei Meng、Jing Hou、Yong-Xian Shao、Pei-Ying Wu、Manna Huang、Xinhai Zhu、Yonghong Cai、Zhe Li、Jie Xu、Peiqing Liu、Hai-Bin Luo、Yiqian Wan、Hengming Ke

  DOI：10.1021/jm301189c

  日期：2012.10.11

  A new series of phosphodiesterase-9 (PDE9) inhibitors that contain a scaffold of 6-amino-pyrazolopyrimidinone have been discovered by a combination of structure-based design and computational docking. This procedure significantly saved the load of chemical synthesis and is an effective method for the discovery of inhibitors. The best compound 28 has an IC50 of 21 nM and 3.3 mu M, respectively, for PDE9 and PDE5 and about 3 orders of magnitude of selectivity against other PDE families. The crystal structure of the PDE9 catalytic domain in complex with 28 has been determined and shows a hydrogen bond between 28 and Tyr424. This hydrogen bond may account for the 860-fold selectivity of 28 against PDE1B, in comparison with about 30-fold selectivity of BAY73-6691. Thus, our studies suggest that Tyr424, a unique residue of PDE8 and PDE9, is a potential target for improvement of selectivity of PDE9 inhibitors.