furan-2-ylmethyl-(3-(morpholin-4-yl)propyl)amine | 442531-34-2

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: furan-2-ylmethyl-(3-(morpholin-4-yl)propyl)amine
• 英文别名: N-(2-furylmethyl)-N-(3-morpholin-4-ylpropyl)amine；N-(furan-2-ylmethyl)-3-morpholin-4-ylpropan-1-amine
• CAS: 442531-34-2
• 化学式: C₁₂H₂₀N₂O₂
• mdl: MFCD01475416
• 分子量: 224.303
• InChiKey: ILBCZZMPZQMCOJ-UHFFFAOYSA-N

物化性质

• 沸点：
  333.4±37.0 °C(Predicted)
• 密度：
  1.060±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  16
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.666
• 拓扑面积：
  37.6
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 危险等级：
  IRRITANT

反应信息

• 作为反应物：
  描述：

  furan-2-ylmethyl-(3-(morpholin-4-yl)propyl)amine 在 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 3.0h， 生成 2-(3-morpholin-4-ylpropyl)-3-oxo-1H-isoindole-4-carboxylic acid
  参考文献：
  名称：

  Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy

  摘要：

  The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-4,4-difluorocyclohexyl)piperidin-4-yl] -6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.

  DOI：

  10.1021/acs.jmedchem.5b00680
• 作为产物：
  描述：

  N-(3-氨丙基)吗啉 、 糠醛 在 sodium tetrahydroborate 作用下， 以 二氯甲烷 、 甲醇 为溶剂， 以86 %的产率得到furan-2-ylmethyl-(3-(morpholin-4-yl)propyl)amine
  参考文献：
  名称：

  新型烟酰胺磷酸核糖转移酶抑制剂的合成及构效关系，对实体癌和血液癌具有抗肿瘤活性

  摘要：

  癌细胞高度依赖烟酰胺磷酸核糖基转移酶 (NAMPT) 活性进行增殖，因此 NAMPT 代表了抗癌药物开发的一个有趣靶点。FK866 和 CHS828 等几种化合物被确定为具有强抗癌活性的强效 NAMPT 抑制剂，尽管它们都没有达到临床试验的后期阶段。我们在此展示了三个新抑制剂库的制备，这些抑制剂包含 (pyridin-3-yl)triazole、(pyridin-3-yl)thiourea 和 (pyridin-3/4-yl)cyanoguanidine 作为帽/连接单元和呋喃基化合物的尾部位置。体外抗增殖活性在一组实体和血液癌细胞系上进行了评估，大多数合成化合物在 MiaPaCa-2（胰腺癌）、ML2（急性髓系白血病）、JRKT（急性淋巴细胞白血病）、NMLW 中显示出纳摩尔或亚纳摩尔的细胞毒活性（Burkitt 淋巴瘤）、RPMI8226（多发性骨髓瘤）和 NB4（急性髓性白血病），IC

  DOI：

  10.1016/j.ejmech.2023.115170

文献信息

• Discovery of 2-[1-(4,4-Difluorocyclohexyl)piperidin-4-yl]-6-fluoro-3-oxo-2,3-dihydro-1<i>H</i>-isoindole-4-carboxamide (NMS-P118): A Potent, Orally Available, and Highly Selective PARP-1 Inhibitor for Cancer Therapy
  作者：Gianluca Papeo、Helena Posteri、Daniela Borghi、Alina A. Busel、Francesco Caprera、Elena Casale、Marina Ciomei、Alessandra Cirla、Emiliana Corti、Matteo D’Anello、Marina Fasolini、Barbara Forte、Arturo Galvani、Antonella Isacchi、Alexander Khvat、Mikhail Y. Krasavin、Rosita Lupi、Paolo Orsini、Rita Perego、Enrico Pesenti、Daniele Pezzetta、Sonia Rainoldi、Federico Riccardi-Sirtori、Alessandra Scolaro、Francesco Sola、Fabio Zuccotto、Eduard R. Felder、Daniele Donati、Alessia Montagnoli

  DOI：10.1021/acs.jmedchem.5b00680

  日期：2015.9.10

  The nuclear protein poly(ADP-ribose) polymerase-1 (PARP-1) has a well-established role in the signaling and repair of DNA and is a prominent target in oncology, as testified by the number of candidates in clinical testing that unselectively target both PARP-1 and its closest isoform PARP-2. The goal of our program was to find a PARP-1 selective inhibitor that would potentially mitigate toxicities arising from cross-inhibition of PARP-2. Thus, an HTS campaign on the proprietary Nerviano Medical Sciences (NMS) chemical collection, followed by SAR optimization, allowed us to discover 2-[1-4,4-difluorocyclohexyl)piperidin-4-yl] -6-fluoro-3-oxo-2,3-dihydro-1H-isoindole-4-carboxamide (NMS-P118, 20by). NMS-P118 proved to be a potent, orally available, and highly selective PARP-1 inhibitor endowed with excellent ADME and pharmacokinetic profiles and high efficacy in vivo both as a single agent and in combination with Temozolomide in MDA-MB-436 and Capan-1 xenograft models, respectively. Cocrystal structures of 20by with both PARP-1 and PARP-2 catalytic domain proteins allowed rationalization of the observed selectivity.
• Synthesis and structure-activity relationship of new nicotinamide phosphoribosyltransferase inhibitors with antitumor activity on solid and haematological cancer
  作者：Simone Fratta、Paulina Biniecka、Antonio J. Moreno-Vargas、Ana T. Carmona、Aimable Nahimana、Michel A. Duchosal、Francesco Piacente、Santina Bruzzone、Irene Caffa、Alessio Nencioni、Inmaculada Robina

  DOI：10.1016/j.ejmech.2023.115170

  日期：2023.3

  Cancer cells are highly dependent on Nicotinamide phosphoribosyltransferase (NAMPT) activity for proliferation, therefore NAMPT represents an interesting target for the development of anti-cancer drugs. Several compounds, such as FK866 and CHS828, were identified as potent NAMPT inhibitors with strong anti-cancer activity, although none of them reached the late stages of clinical trials. We present

  癌细胞高度依赖烟酰胺磷酸核糖基转移酶 (NAMPT) 活性进行增殖，因此 NAMPT 代表了抗癌药物开发的一个有趣靶点。FK866 和 CHS828 等几种化合物被确定为具有强抗癌活性的强效 NAMPT 抑制剂，尽管它们都没有达到临床试验的后期阶段。我们在此展示了三个新抑制剂库的制备，这些抑制剂包含 (pyridin-3-yl)triazole、(pyridin-3-yl)thiourea 和 (pyridin-3/4-yl)cyanoguanidine 作为帽/连接单元和呋喃基化合物的尾部位置。体外抗增殖活性在一组实体和血液癌细胞系上进行了评估，大多数合成化合物在 MiaPaCa-2（胰腺癌）、ML2（急性髓系白血病）、JRKT（急性淋巴细胞白血病）、NMLW 中显示出纳摩尔或亚纳摩尔的细胞毒活性（Burkitt 淋巴瘤）、RPMI8226（多发性骨髓瘤）和 NB4（急性髓性白血病），IC