1-(4-(苄基氨基)-7,8-二氢-5H-吡喃并[4,3-D]嘧啶-2-基)-2-甲基-1H-吲哚-4-甲酰胺 | 1542705-92-9

• 物质功能分类: 生物化工 - 生化试剂 - 激动剂抑制剂
• 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
• 中文名称: 1-(4-(苄基氨基)-7,8-二氢-5H-吡喃并[4,3-D]嘧啶-2-基)-2-甲基-1H-吲哚-4-甲酰胺
• 中文别名: CB5083抑制剂；P97抑制剂(CB-5083)
• 英文名称: CB-5083
• 英文别名: 1-[4-(benzylamino)-5H,7H,8H-pyrano[4,3-d]pyrimidin-2-yl]-2-methyl-1H-indole-4-carboxamide；Cb-5083；1-[4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl]-2-methylindole-4-carboxamide
• CAS: 1542705-92-9
• 化学式: C₂₄H₂₃N₅O₂
• mdl: MFCD28963914
• 分子量: 413.479
• InChiKey: RDALZZCKQFLGJP-UHFFFAOYSA-N

物化性质

• 沸点：
  760.5±70.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Predicted)
• 溶解度：
  不溶于水； DMSO 中≥20.65 mg/mL；乙醇中≥4.4 mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  95.1
• 氢给体数：
  2
• 氢受体数：
  5

安全信息

• 危险性防范说明：
  P261,P280,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H332,H335
• 储存条件：
  -20℃

制备方法与用途

生物活性

CB-5083是一种有效的、选择性的且口服具有生物活性的p97 AAA ATPase抑制剂，其IC50值为11 nM。该药物处于一期临床阶段。

靶点

Target	Value
p97 AAA ATPase (Cell-free assay)	11 nM

体外研究

在A549细胞中，CB-5083显著引起K48聚泛素化蛋白和CHOP的积累，并导致p62减少。其IC50值为680 nM。

体内研究

在小鼠负载的人HCT 116结肠癌异种移植物中，CB-5083 (75 mg/kg, p.o.)显著抑制肿瘤生长。同样，在负载成熟的人AMO-1多发性骨髓瘤和A549肺癌肿瘤移植物的小鼠中，CB-5083 (100 mg/kg, p.o.)也会导致显著的肿瘤生长抑制。

反应信息

• 作为反应物：
  描述：

  1-(4-(苄基氨基)-7,8-二氢-5H-吡喃并[4,3-D]嘧啶-2-基)-2-甲基-1H-吲哚-4-甲酰胺 在 劳森试剂 作用下， 以 四氢呋喃 为溶剂， 以81%的产率得到1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H -indole-4-carbothioamide
  参考文献：
  名称：

  Discovery of a new class of valosine containing protein (VCP/P97) inhibitors for the treatment of non-small cell lung cancer

  摘要：

  Valosine containing protein (VCP/p97) is a member of the AAA ATPase family involved in several essential cellular functions and plays an important role in the ubiquitin-mediated degradation of misfolded proteins. P97 has a significant role in maintaining the cellular protein homeostasis for tumor cell growth and survival and has been found overexpressed in many tumor types. No new molecule entities based on p97 target were approved in clinic. Herein, a series of novel pyrimidine structures as p97 inhibitors were designed and synthesized. After enzymatic evaluations, structure-activity relationships (SAR) were discussed in detailed. Among the screened compounds, derivative 35 showed excellent enzymatic inhibitory activity (IC50, 36 nM). The cellular inhibition results showed that compound 35 had good antiproliferative activity against the non-small cell lung cancer A549 cells (IC50, 1.61 mu M). Liver microsome stability showed that the half-life of compound 35 in human liver microsome was 42.3 min, which was more stable than the control CB-5083 (25.8 min). The in vivo pharmacokinetic results showed that the elimination phase half-lives of compound 35 were 4.57 h for ig and 3.64 h for iv, respectively and the oral bioavailability was only 4.5%. These results indicated that compound 35 could be effective for intravenous treatment of non-small cell lung cancer.

  DOI：

  10.1016/j.bmc.2018.12.036
• 作为产物：
  描述：

  1-(4-(benzylamino)-7,8-dihydro-5H-pyrano[4,3-d]pyrimidin-2-yl)-2-methyl-1H-indole-4-carbonitrile 以58的产率得到1-(4-(苄基氨基)-7,8-二氢-5H-吡喃并[4,3-D]嘧啶-2-基)-2-甲基-1H-吲哚-4-甲酰胺
  参考文献：
  名称：

  FUSED PYRIMIDINES AS INHIBITORS OF P97 COMPLEX

  摘要：

  本发明公开了一种融合嘧啶化合物，其具有饱和，不饱和或芳香性A环融合到嘧啶环上，并在嘧啶环的2位位置具有复杂的取代基和取代胺在嘧啶环的4位位置，以及可选的脂肪烷基，功能性和/或芳香基组分取代在嘧啶环和A环的其他位置。这些化合物是AAA蛋白酶复合物的抑制剂，包含p97，并且是用于治疗与p97生物活性相关的疾病的有效药物，例如癌症。

  公开号：

  US20170258795A1

文献信息

• [EN] FUSED PYRIMIDINES AS INHIBITORS OF p97 COMPLEX<br/>[FR] PYRIMIDINES FUSIONNÉES EN TANT QU'INHIBITEURS DU COMPLEXE P97
  申请人：ZHOU HAN-JIE

  公开号：WO2014015291A1

  公开（公告）日：2014-01-23

  Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

  本发明揭示了一种融合嘧啶化合物，其具有饱和、不饱和或芳香性A环与嘧啶环融合，并在嘧啶环的2位具有复杂的取代基，在4位具有取代胺基，以及在其他位置可选地具有取代的脂肪族、功能性和/或芳香性组分的嘧啶环和A环。这些化合物是包含p97的AAA蛋白酶复合物的抑制剂，是治疗与p97生物活性相关的疾病如癌症的有效药物。
• Fused pyrimidines as inhibitors of P97 complex
  申请人：Cleave Biosciences, Inc.

  公开号：US10010554B2

  公开（公告）日：2018-07-03

  Fused pyrimidine compounds having a saturated, unsaturated or aromatic A ring fused to a pyrimidine ring and having a complex substituents at the 2 position and a substituted amine at the 4 position of the pyrimidine ring as well as optional aliphatic, functional and/or aromatic components substituted at other positions of the pyrimidine ring and A ring are disclosed. These compounds are inhibitors of the AAA proteasome complex containing p97 and are effective medicinal agents for treatment of diseases associated with p97 bioactivity such as cancer.

  本发明公开了具有与嘧啶环融合的饱和、不饱和或芳香 A 环的融合嘧啶化合物，该化合物在嘧啶环的 2 位具有复合取代基，在 4 位具有取代胺，并在嘧啶环和 A 环的其他位置具有任选取代的脂肪族、官能团和/或芳香族成分。这些化合物是含有 p97 的 AAA 蛋白酶体复合物的抑制剂，是治疗与 p97 生物活性有关的疾病（如癌症）的有效药物。
• Discovery of a First-in-Class, Potent, Selective, and Orally Bioavailable Inhibitor of the p97 AAA ATPase (CB-5083)
  作者：Han-Jie Zhou、Jinhai Wang、Bing Yao、Steve Wong、Stevan Djakovic、Brajesh Kumar、Julie Rice、Eduardo Valle、Ferdie Soriano、Mary-Kamala Menon、Antonett Madriaga、Szerenke Kiss von Soly、Abhinav Kumar、Francesco Parlati、F. Michael Yakes、Laura Shawver、Ronan Le Moigne、Daniel J. Anderson、Mark Rolfe、David Wustrow

  DOI：10.1021/acs.jmedchem.5b01346

  日期：2015.12.24

  The AAA-ATPase p97 plays vital roles in mechanisms of protein homeostasis, including ubiquitin proteasome system (ups) mediated protein degradation, endoplasmic reticulum-associated degradation (BRAD), and autophagy. Herein we describe our lead optimization efforts focused on in vitro potency, ADME, and pharmaceutical properties that led to the discovery of a potent, ATP-competitive, D2-selective, and orally bioavailable p97 inhibitor 71, CB-6083. Treatment of tumor cells with 71 leads to significant accumulation of markers associated with inhibition of UPS and ERAD functions, which induces irresolvable proteotoxic stress and cell, death. In tumor bearing mice, oral administration of 71 causes rapid accumulation Of markers of the unfolded protein response (UPR) and subsequently induces apoptosis leading to Sustained antitumor activity in in vivo, xenograft models of both solid and hematological tumors. 71 has been taken into phase I clinical trials in patients with multiple myeloma and solid tumors.
• J. Med. Chem. 2015, 58, 9480-9497
  作者：

  DOI：——

  日期：——
• FUSED PYRIMIDINES AS INHIBITORS OF p97 COMPLEX
  申请人：Cleave Biosciences, Inc.

  公开号：EP2875018B1

  公开（公告）日：2018-02-14