3-甲基-N-[1,4,5,6-四氢-6,6-二甲基-5-[(1-甲基-4-哌啶基)甲酰基]吡咯并[3,4-C]吡唑-3-基]丁酰胺 | 718630-59-2

• 物质功能分类: 生物化工 - 抑制剂 - 细胞周期(Cell Cycle)
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 中文名称: 3-甲基-N-[1,4,5,6-四氢-6,6-二甲基-5-[(1-甲基-4-哌啶基)甲酰基]吡咯并[3,4-C]吡唑-3-基]丁酰胺
• 英文名称: PHA-793887
• 英文别名: N-(6,6-dimethyl-5-(1-methylpiperidine-4-carbonyl)-1,4,5,6-tetrahydropyrrolo[3,4-c]pyrazol-3-yl)-3-methylbutanamide；N-[6,6-dimethyl-5-(1-methylpiperidine-4-carbonyl)-1,4-dihydropyrrolo[3,4-c]pyrazol-3-yl]-3-methylbutanamide
• CAS: 718630-59-2
• 化学式: C₁₉H₃₁N₅O₂
• 分子量: 361.487
• InChiKey: HUXYBQXJVXOMKX-UHFFFAOYSA-N

物化性质

• 熔点：
  >147°C (dec.)
• 沸点：
  596.2±50.0 °C(Predicted)
• 密度：
  1.176±0.06 g/cm3(Predicted)
• 溶解度：
  DMSO（微溶）、甲醇（微溶）

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  81.3
• 氢给体数：
  2
• 氢受体数：
  4

安全信息

• 危险性防范说明：
  P261,P305+P351+P338
• 危险性描述：
  H302,H315,H319,H335

制备方法与用途

生物活性

PHA-793887是一种新型有效的CDK2、CDK5和CDK7抑制剂，IC50分别为8 nM、5 nM 和10 nM。其对CDK2、5和7的选择性比作用于CDK1、4和9高6倍以上。Phase 1。

体外研究

PHA-793887能够抑制多种肿瘤细胞系的增殖，包括A2780、HCT-116、COLO-205、C-433、DU-145、A375、PC3、MCF-7和BX-PC3，其IC50范围为88 nM至3.4 μM。此外，在白血病细胞系K562、KU812、KCL22和TOM1中表现出细胞毒性作用，IC50值在0.3至7 μM之间。然而，在正常未受刺激处理的外周血单核细胞或CD34+造血干细胞中没有显示细胞毒性。PHA-793887对白血病细胞系显示出高活性，IC50< 0.1 μM。该药物还能够诱导细胞周期停滞、抑制Rb和核磷蛋白磷酸化，在0.2至1 μM时调节cyclin E和cdc6的表达，并在5 μM时诱导凋亡。

体内研究

PHA-793887(10–30 mg/kg)在人类卵巢癌A2780、结肠癌HCT-116和胰脏癌BX-PC3移植瘤模型中表现出高效性。在携带K562和HL60细胞的移植瘤模型、原代白血病扩散细胞模型以及复发Philadelphia-阳性急性淋巴性白血病患者体内获得的高负担扩散性ALL-2模型中，PHA-793887(20 mg/kg)同样表现出高效性。

特征

PHA-793887是一种新型有效的二代CDK抑制剂。其在体外和体内实验中的表现均显示出良好的生物活性与选择性。

靶点

Target	Value
CDK5/p25	5 nM
CDK2/CyclinA	8 nM
CDK2/CyclinE	8 nM
CDK7/CyclinH	10 nM
CDK1/CyclinB	60 nM

反应信息

• 作为产物：
  描述：

  在 甲醇 、 三乙胺 作用下， 生成 3-甲基-N-[1,4,5,6-四氢-6,6-二甲基-5-[(1-甲基-4-哌啶基)甲酰基]吡咯并[3,4-C]吡唑-3-基]丁酰胺
  参考文献：
  名称：

  Optimization of 6,6-dimethyl pyrrolo[3,4-c]pyrazoles: Identification of PHA-793887, a potent CDK inhibitor suitable for intravenous dosing

  摘要：

  We have recently reported CDK inhibitors based on the 6-substituted pyrrolo[3,4-c]pyrazole core structure. Improvement of inhibitory potency against multiple CDKs, antiproliferative activity against cancer cell lines and optimization of the physico-chemical properties led to the identification of highly potent compounds. Compound 31 (PHA-793887) showed good efficacy in the human ovarian A2780, colon HCT-116 and pancreatic BX-PC3 carcinoma xenograft models and was well tolerated upon daily treatments by iv administration. It was identified as a drug candidate for clinical evaluation in patients with solid tumors.

  DOI：

  10.1016/j.bmc.2010.01.042

文献信息

• COMPOUNDS AND METHODS FOR TREATMENT AND PREVENTION OF FLAVIVIRUS INFECTION
  申请人：FLORIDA STATE UNIVERSITY RESEARCH FOUNDATION, INC.

  公开号：US20180015153A1

  公开（公告）日：2018-01-18

  The present invention concerns the use of compounds for the treatment or prevention of Flavivirus infections, such as Zika virus infections. Aspects of the invention include methods for treating or preventing Flavivirus virus infection, such as Zika virus infection, by administering a compound or class of compound disclosed herein, such as a niclosamide compound, an emricasan compound, a cyclin-dependent kinase inhibitor, a proteasome inhibitor, or a combination of two or more of the foregoing, to a subject in need thereof; methods for inhibiting Flavivirus infections such as Zika virus infections in a cell in vitro or in vivo; pharmaceutical compositions; packaged dosage formulations; and kits for treating or preventing Flavivirus infections, such Zika virus infections.

  本发明涉及化合物用于治疗或预防黄病毒感染，如寨卡病毒感染。该发明的方面包括通过给予本文所披露的化合物或化合物类别，如尼克洛酰胺化合物、恩米卡珊化合物、细胞周期依赖性激酶抑制剂、蛋白酶体抑制剂或前述两种或更多的组合，治疗或预防黄病毒感染，如寨卡病毒感染的方法；在体外或体内抑制黄病毒感染，如寨卡病毒感染的方法；制药组合；包装剂量配方；以及用于治疗或预防黄病毒感染，如寨卡病毒感染的工具包。
• [EN] QUINOLINYL-PYRAZINE-CARBOXAMIDE COMPOUNDS AND USES THEREOF<br/>[FR] COMPOSÉS DE QUINOLINYL-PYRAZINE-CARBOXAMIDE ET UTILISATIONS ASSOCIÉES
  申请人：UNIV MICHIGAN REGENTS

  公开号：WO2020132459A1

  公开（公告）日：2020-06-25

  This invention is in the field of medicinal chemistry. In particular, the invention relates to a new class of small-molecules having a quinolinyl-pyrazine-carboxamide (or similar) structure which function as activators of the cholesterol biosynthesis pathway within cancer cells and/or immune cells, which function as activators of the cell cycle regulation pathway within cancer cells and/or immune cells, and which function as up-regulators of HMGCS1 protein expression within cancer cells and/or immune cells, and which function as effective therapeutic agents for treating, ameliorating, and preventing various forms of cancer and other inflammatory disease.

  这项发明属于药物化学领域。具体来说，该发明涉及一类新型小分子，其具有喹啉基-吡嗪-羧酰胺（或类似）结构，其在癌细胞和/或免疫细胞内作为胆固醇生物合成途径的激活剂，作为癌细胞和/或免疫细胞内细胞周期调控途径的激活剂，作为癌细胞和/或免疫细胞内HMGCS1蛋白表达的上调剂，以及作为治疗、改善和预防各种癌症和其他炎症性疾病的有效治疗剂。
• Substituted pyrrolo-pyrazole derivatives as kinase inhibitors
  申请人：Brasca Gabriella Maria

  公开号：US20070004705A1

  公开（公告）日：2007-01-04

  Compounds represented by formula (Ia) or (Ib) and wherein R and R 1 are as defined in the description, and pharmaceutically acceptable salts thereof, are disclosed; the said compounds are useful in the treatment of cell cycle proliferative disorders, e.g. cancer, associated with an altered cell cycle dependent kinase activity.

  本发明公开了由式(Ia)或(Ib)所代表的化合物，其中R和R1如说明书所定义，并且其药学上可接受的盐。所述化合物可用于治疗与细胞周期依赖性激酶活性改变相关的细胞周期增殖性疾病，例如癌症。
• Maturation of hepatocyte-like cells derived from human pluripotent stem cells
  申请人：Takara Bio Europe AB

  公开号：US10294457B2

  公开（公告）日：2019-05-21

  The present invention relates to directed differentiation and maturation of hepatocyte-like cells. In particular, the present invention relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of GSK-3 (Glycogen synthase kinase 3) or activator of Wnt signalling and/or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The present invention also relates to exposure of hepatocyte-like cells to an activator of a retinoic acid responsive receptor, such as retinoic acid (RA), optionally in combination with an inhibitor of a cycline dependent kinase (CDK) and/or with the overlay of the cells with one or more components characteristic of the mammalian extracellular matrix (matrix overlay). The hepatocyte-like cells obtained in accordance with the present invention show a phenotype which is more similar to that of primary hepatocytes than previously shown.

  本发明涉及肝细胞样细胞的定向分化和成熟。特别是，本发明涉及将肝细胞样细胞暴露于视黄酸反应受体的激活剂，如视黄酸（RA），可选择与 GSK-3（糖原合酶激酶 3）抑制剂或 Wnt 信号激活剂结合使用，和/或将细胞与哺乳动物细胞外基质的一种或多种特征成分（基质覆盖）结合使用。本发明还涉及将肝细胞样细胞暴露于视黄酸反应受体的激活剂，如视黄酸（RA），可选择与细胞周期依赖性激酶（CDK）抑制剂结合使用，和/或将细胞与哺乳动物细胞外基质的一种或多种特征成分覆盖（基质覆盖）。根据本发明获得的肝细胞样细胞显示出的表型比以前显示的更类似于原代肝细胞的表型。
• Compounds and methods for treatment and prevention of Flavivirus infection
  申请人：FLORIDA STATE UNIVERSITY RESEARCH FOUNDATION, INC.

  公开号：US10940188B2

  公开（公告）日：2021-03-09

  The present invention concerns the use of compounds for the treatment or prevention of Flavivirus infections, such as Zika virus infections. Aspects of the invention include methods for treating or preventing Flavivirus virus infection, such as Zika virus infection, by administering a compound or class of compound disclosed herein, such as a niclosamide compound, an emricasan compound, a cyclin-dependent kinase inhibitor, a proteasome inhibitor, or a combination of two or more of the foregoing, to a subject in need thereof; methods for inhibiting Flavivirus infections such as Zika virus infections in a cell in vitro or in vivo; pharmaceutical compositions; packaged dosage formulations; and kits for treating or preventing Flavivirus infections, such Zika virus infections.

  本发明涉及使用化合物治疗或预防弗拉维病毒感染，如寨卡病毒感染。本发明的方面包括通过向有需要的受试者施用本文公开的化合物或化合物类别，如烟酰胺化合物、依木酰胺化合物、细胞周期蛋白依赖性激酶抑制剂、蛋白酶体抑制剂或上述两种或多种的组合，治疗或预防弗拉维病毒感染，如寨卡病毒感染的方法；抑制体外或体内细胞中黄病毒感染（如寨卡病毒感染）的方法；药物组合物；包装剂型；以及治疗或预防黄病毒感染（如寨卡病毒感染）的试剂盒。