2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one | 1449597-34-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶并嘧啶类
• 英文名称: 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
• 英文别名: SMN-C3；Unii-MV8T2mck57；2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methylpyrido[1,2-a]pyrimidin-4-one
• CAS: 1449597-34-5
• 化学式: C₂₄H₂₈N₆O
• 分子量: 416.526
• InChiKey: ZACWYYKZMLGOTG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  66.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  3,5-吡唑羧酸二乙酯 在 1,3-bis[(diphenylphosphino)propane]dichloronickel(II) 、 ammonium acetate 、 4-甲基苯磺酸吡啶 、 三乙酰氧基硼氢化钠 、 potassium carbonate 、 溶剂黄146 、 lithium hexamethyldisilazane 、 三氯氧磷 作用下， 以 四氢呋喃 、 乙醇 、 异戊醇 、 二氯甲烷 、 乙基苯 、 丙酮 为溶剂， 反应 117.67h， 生成 2-(4,6-dimethylpyrazolo[1,5-a]pyrazin-2-yl)-7-(1-ethylpiperidin-4-yl)-9-methyl-4H-pyrido[1,2-a]pyrimidin-4-one
  参考文献：
  名称：

  Specific Correction of Alternative Survival Motor Neuron 2 Splicing by Small Molecules: Discovery of a Potential Novel Medicine To Treat Spinal Muscular Atrophy

  摘要：

  Spinal muscular atrophy (SMA) is the leading genetic cause of infant and toddler mortality, and there is currently no approved therapy available. SMA is caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. These mutations or deletions result in low levels of functional SMN protein. SMN2, a paralogous gene to SMN1, undergoes alternative splicing and exclusion of exon 7, producing an unstable, truncated SMI\T07 protein. Herein, we report the identification of a pyridopyrimidinone series of small molecules that modify the alternative splicing of SMN2, increasing the production of fulllength SMN2 mRNA. Upon oral administration of our small molecules, the levels of fulllength SMN protein were restored in two mouse models of SMA. In-depth lead optimization in the pyridopyrimidinone series culminated in the selection of compound 3 (RG7800), the first small molecule SMN2 splicing modifier to enter human clinical trials.

  DOI：

  10.1021/acs.jmedchem.6b00459

文献信息

• COMPOUNDS FOR TREATING SPINAL MUSCULAR ATROPHY
  申请人：PTC Therapeutics, Inc.

  公开号：US20180105526A1

  公开（公告）日：2018-04-19

  Provided herein are compounds, compositions thereof and uses therewith for treating spinal muscular atrophy.

  本文提供了用于治疗脊髓性肌萎缩症的化合物、其组成物和使用方法。
• Methods for modulating the amount of RNA transcripts
  申请人：PTC Therapeutics, Inc.

  公开号：US10195202B2

  公开（公告）日：2019-02-05

  Described herein are methods for modulating the amount of a gene product and compounds for use in such methods. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product as the result of gene expression and compounds for use in such methods.

  本文描述的是调节基因产物量的方法和用于此类方法的化合物。更具体地说，这里描述的是调节作为基因表达结果的 RNA 转录物或蛋白质产物量的方法和用于这种方法的化合物。
• Methods for modulating RNA splicing
  申请人：PTC Therapeutics, Inc.

  公开号：US10668171B2

  公开（公告）日：2020-06-02

  In one aspect, described herein is a recognition element for splicing modifier (REMS) that can be recognized by a compound provided herein. In another aspect, described herein are methods for modulating the amount of a product of a gene, wherein a precursor RNA transcript transcribed from the gene contains a REMS, and the methods utilizing a compound described herein. More particularly, described herein are methods for modulating the amount of an RNA transcript or protein product encoded by a gene, wherein a precursor RNA transcript transcribed from the gene comprises a REMS, and the methods utilizing a compound described herein. In another aspect, provided herein are artificial gene constructs comprising a REMS, and uses of those artificial gene constructs to modulate functional protein production. In another aspect, provided herein are methods for altering endogenous genes to comprise a REMS, and the use of a compound described herein to modulate the functional protein produced from such altered endogenous genes.

  一方面，本文描述了一种可被本文提供的化合物识别的剪接修饰物（REMS）识别元件。另一方面，本文所述的是调节基因产物量的方法，其中从基因转录的前体 RNA 转录本含有 REMS，该方法利用本文所述的化合物。更具体地说，本文所述的是调节由基因编码的 RNA 转录物或蛋白质产物量的方法，其中由基因转录的前体 RNA 转录物含有 REMS，以及利用本文所述化合物的方法。另一方面，本文提供了包含 REMS 的人工基因构建体，以及利用这些人工基因构建体调节功能性蛋白质生产的方法。另一个方面，本文提供了改变内源基因使其包含 REMS 的方法，以及利用本文所述化合物调节由这种改变的内源基因产生的功能蛋白的方法。
• Compounds for treating spinal muscular atrophy
  申请人：PTC Therapeutics, Inc.

  公开号：US10851101B2

  公开（公告）日：2020-12-01

  Provided herein are compounds of Formula (I): and forms thereof, including compositions thereof and uses therewith for treating spinal muscular atrophy.

  本文提供的是式 (I) 化合物： 及其形式，包括其组合物和用途，用于治疗脊髓性肌萎缩症。
• Methods for treating Huntington's Disease
  申请人：PTC Therapeutics, Inc.

  公开号：US11382918B2

  公开（公告）日：2022-07-12

  The present description relates to a method or use of a compound for treating or ameliorating HD (Huntington's Disease) in a subject in need thereof comprising administering to the subject an effective amount of a compound of Formula (I): or a form thereof, wherein w1, w2, w3, w4, w5, w6 and w7 are as defined herein. In particular, the present description relates to a method of use of a compound of Formula (I) or a form or composition thereof for treating or ameliorating HD in a subject in need thereof comprising, administering an effective amount of the compound or a form or composition thereof to the subject.

  本说明书涉及一种化合物治疗或改善有需要的受试者的 HD（亨廷顿氏病）的方法或用途，包括向受试者施用有效量的式（I）化合物： 或其形式，其中 w1、w2、w3、w4、w5、w6 和 w7 如本文所定义。特别是，本说明涉及一种使用式（I）化合物或其形式或组合物治疗或改善有需要的受试者的 HD 的方法，包括向受试者施用有效量的化合物或其形式或组合物。