5'-methyl-2'-(biphenylmethyl)-3'-(phenylmethyl)spiro[cyclopentane-1,7'(8'H)-[3H]imidazo[2,1-b]purin]-4'(5'H)-one | 191982-37-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 5'-methyl-2'-(biphenylmethyl)-3'-(phenylmethyl)spiro[cyclopentane-1,7'(8'H)-[3H]imidazo[2,1-b]purin]-4'(5'H)-one
• 英文别名: 5'-methyl-2'-(biphenylmethyl)-3'-(phenylmethyl)spiro[cyclopentane-1,7(8'H)-[3H]imidazo[2,1-b]purin]-4(5'H)-one；3-benzyl-5-methyl-2-[(4-phenylphenyl)methyl]spiro[8H-imidazo[2,1-b]purine-7,1'-cyclopentane]-4-one
• CAS: 191982-37-3
• 化学式: C₃₂H₃₁N₅O
• 分子量: 501.631
• InChiKey: RRRMTTFOHGYQIH-UHFFFAOYSA-N

物化性质

• 沸点：
  721.4±70.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.5
• 重原子数：
  38
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  53.7
• 氢给体数：
  0
• 氢受体数：
  3

制备方法与用途

PDE1-IN-1能够提高第二信使cAMP/cGMP的水平，从而促进神经元可塑性相关基因、神经营养因子以及神经保护分子的表达。这些增强的神经元可塑性特性使得PDE1抑制剂成为治疗多种神经系统疾病的良好候选药物。

反应信息

• 作为反应物：
  描述：

  5'-methyl-2'-(biphenylmethyl)-3'-(phenylmethyl)spiro[cyclopentane-1,7'(8'H)-[3H]imidazo[2,1-b]purin]-4'(5'H)-one 在 palladium dihydroxide ammonium formate 作用下， 以 甲醇 为溶剂， 生成 5'-methyl-2'-(biphenylmethyl)spiro[cyclopentane-1,7(8'H)-[3H]imidazo[2,1-b]purin]-4(5'H)-one
  参考文献：
  名称：

  Potent Tetracyclic Guanine Inhibitors of PDE1 and PDE5 Cyclic Guanosine Monophosphate Phosphodiesterases with Oral Antihypertensive Activity

  摘要：

  Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).

  DOI：

  10.1021/jm9608467
• 作为产物：
  描述：

  4-联苯乙酸 在 4-二甲氨基吡啶 、 氯化亚砜 、 N-ethyl-N’-(diethylaminopropyl)-carbodiimide 、 N,N-二异丙基乙胺 、 三氯氧磷 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 10.0h， 生成 5'-methyl-2'-(biphenylmethyl)-3'-(phenylmethyl)spiro[cyclopentane-1,7'(8'H)-[3H]imidazo[2,1-b]purin]-4'(5'H)-one
  参考文献：
  名称：

  Potent Tetracyclic Guanine Inhibitors of PDE1 and PDE5 Cyclic Guanosine Monophosphate Phosphodiesterases with Oral Antihypertensive Activity

  摘要：

  Tetracyclic guanines have been shown to be potent and selective inhibitors of the cGMP-hydrolyzing enzymes PDE1 and PDE5. In general, these compounds are inactive or only weakly active as inhibitors of PDE3, which is a major isozyme involved in cAMP hydrolysis. Structure-activity relationships are developed at N-1, C-2, N-3, and N-5 on the core nucleus. Compound 31, with an IC50 of 70 pM, is the most potent inhibitor of PDE1, while 50, with an IC50 of 4 nM, is the most potent inhibitor of PDE5. Compounds 20, 22, 30, and 50 are potent dual inhibitors with IC50 values below 30 nM for both PDE1 and PDE5. Compounds 12, 20, and 28 reduced blood pressure by more than 45 mmHg when administered orally at 10 mg/kg to the spontaneously hypertensive rat (SHR).

  DOI：

  10.1021/jm9608467

文献信息

• [EN] POLYCYCLIC GUANINE DERIVATIVE PHOSPHODIESTERASE V INHIBITORS<br/>[FR] INHIBITEURS DE LA PHOSPHODIESTERASE V DE DERIVES POLYCYCLIQUES DE GUANINE
  申请人：SCHERING CORP

  公开号：WO2003042216A1

  公开（公告）日：2003-05-22

  A compound having the formula (Ia) or (b), salt or solvate thereof, with the variables as defined herein, which can inhibit selectively phosphodiesterase V and can be useful for treating sexual dysfunction and other physiological disorders, symptoms and diseases

  具有化学式(Ia)或(b)的化合物，其盐或溶剂化物，其中变量的定义如此，可以选择性地抑制磷酸二酯酶V，并可用于治疗性功能障碍和其他生理障碍、症状和疾病。
• Organic compounds
  申请人：Fienberg Allen A.

  公开号：US10010553B2

  公开（公告）日：2018-07-03

  The present invention relates to a new use of phosphodiesterase 1 (PDE1) inhibitors for the treatment of psychosis, schizophrenia, schizoaffective disorder, schizophreniform disorder, psychotic disorder, delusional disorder, mania, or bipolar disorder.

  本发明涉及一种磷酸二酯酶1（PDE1）抑制剂的新用途，用于治疗精神病、精神分裂症、情感分裂症、精神分裂症、精神病性障碍、妄想性障碍、躁狂症或双相情感障碍。
• Uses
  申请人：INTRA-CELLULAR THERAPIES, INC.

  公开号：US10183023B2

  公开（公告）日：2019-01-22

  The subject matter generally relates to methods of treatment and/or prophylaxis of CNS diseases, disorders, and/or injuries. In one aspect, the subject matter relates to inhibitors of phosphodiesterase 1 (PDE1) as neuroprotective agents and/or neural regenerative agents. In a further aspect, the subject matter relates to individuals that are at risk for the development of CNS disease or disorder.

  本课题一般涉及中枢神经系统疾病、失调和/或损伤的治疗和/或预防方法。 在一个方面，该主题涉及作为神经保护剂和/或神经再生剂的磷酸二酯酶 1 (PDE1) 抑制剂。 在另一个方面，该主题涉及有中枢神经系统疾病或紊乱发生风险的个体。
• Combinations of PDE1 inhibitors and NEP inhibitors and associated methods
  申请人：Intra-Cellular Therapies, Inc.

  公开号：US10285992B2

  公开（公告）日：2019-05-14

  The invention relates to the combination of inhibitors of phosphodiesterase 1 (PDE1) and inhibitors of Neprilysin (NEP) useful for the treatment of certain cardiovascular diseases or related disorders, e.g., hypertension, congestive heart disease, and post-myocardial infarction. In another embodiment, the invention relates to the combination of inhibitors of PDE1 and inhibitors of NEP for the treatment of diseases or disorders characterized by disruption of or damage to various cGMP/PKG mediated pathways in the cardiovascular system (e.g., in cardiac tissue or in arterial smooth muscle).

  本发明涉及磷酸二酯酶1（PDE1）抑制剂和NEPrilysin（NEP）抑制剂的组合，用于治疗某些心血管疾病或相关疾病，如高血压、充血性心脏病和心肌梗塞后。在另一个实施方案中，本发明涉及 PDE1 抑制剂和 NEP 抑制剂的组合，用于治疗以心血管系统（如心脏组织或动脉平滑肌）中各种 cGMP/PKG 介导的通路被破坏或损害为特征的疾病或紊乱。
• Combinations of PDE1 inhibitors and NEP inhibitors
  申请人：INTRA-CELLULAR THERAPIES, INC.

  公开号：US11166956B2

  公开（公告）日：2021-11-09

  The invention relates to the combination of inhibitors of phosphodiesterase 1 (PDE1) and inhibitors of Neprilysin (NEP) useful for the treatment of certain cardiovascular diseases or related disorders, e.g., hypertension, congestive heart disease, and post-myocardial infarction. In another embodiment, the invention relates to the combination of inhibitors of PDE1 and inhibitors of NEP for the treatment of diseases or disorders characterized by disruption of or damage to various cGMP/PKG mediated pathways in the cardiovascular system (e.g., in cardiac tissue or in arterial smooth muscle).

  本发明涉及磷酸二酯酶1（PDE1）抑制剂和NEPrilysin（NEP）抑制剂的组合，用于治疗某些心血管疾病或相关疾病，如高血压、充血性心脏病和心肌梗塞后。在另一个实施方案中，本发明涉及 PDE1 抑制剂和 NEP 抑制剂的组合，用于治疗以心血管系统（如心脏组织或动脉平滑肌）中各种 cGMP/PKG 介导的通路被破坏或损害为特征的疾病或紊乱。