N-(5-cyclobutyl-2H-pyrazol-3-yl)-2-naphthalene-2-yl-acetamide | 865317-30-2

• 物质功能分类: 生物化工 - 抑制剂
• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-(5-cyclobutyl-2H-pyrazol-3-yl)-2-naphthalene-2-yl-acetamide
• 英文别名: CDK5 inhibitor 20-223；N-(5-cyclobutyl-1H-pyrazol-3-yl)-2-naphthalen-2-ylacetamide
• CAS: 865317-30-2
• 化学式: C₁₉H₁₉N₃O
• 分子量: 305.379
• InChiKey: AGVIDDQHAQSPIZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  57.8
• 氢给体数：
  2
• 氢受体数：
  2

制备方法与用途

生物活性

CDK5 inhibitor 20-223 是一种有效的 CDK2 和 CDK5 抑制剂，IC50 分别为 6.0 和 8.8 nM。CDK5 inhibitor 20-223 有潜力用于结肠直肠癌 (CRC) 的研究。

靶点

CDK2 6.0 nM (IC 50 )

CDK5 8.8 nM (IC 50 )

体外研究

CDK5 inhibitor 20-223 (10 nM-10 μM; 72 hours) potently inhibits cell growth in a panel of colorectal cancer (CRC) cell lines.
CDK5 inhibitor 20-223 (0.3125-20 μM; 6 hours) induces a dose-dependent decrease in pRB (S807/811) and pFAK (S732) levels in each of the three CRC cell lines.

Cell Viability Assay

Cell Line:	CRC cell lines SW620, DLD1, HT29, HCT116, FET, CBS, and GEO cells
Concentration:	10 μM, 1 μM, 100 nM, 10 nM
Incubation Time:	72 hours
Result:	Reduced cell growth. IC50s of 168±20, 480±41, 360±72, 763±92, 117±49, 568±49, 79±31 nM for SW620, DLD1, HT29, HCT116, FET, CBS, and GEO cells.

Western Blot Analysis

Cell Line:	CRC cell lines GEO, HCT116 and HT29
Concentration:	20, 10, 5, 2.5, 1.25, 0.625, 0.3125 μM
Incubation Time:	6 hours
Result:	Did not affect the total levels of CDK2/5, and the levels of total FAK or total Retinoblastoma protein (Rb). Induced a dose-dependent decrease in pRB (S807/811) and pFAK (S732) levels.

体内研究

CDK5 inhibitor 20-223 (8mg/kg; subcutaneously; for 14 injections) shows anti-tumor activity in human CRC xenograft tumors in nude mice.

Animal Model:	Athymic nude mice
Dosage:	8 mg/kg
Administration:	Injections were given subcutaneously daily for the first week and every other day for two more weeks for a total of 14 injections.
Result:	Reduced tumor growth and tumor weight in vivo.

反应信息

• 作为产物：
  描述：

  在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 N-(5-cyclobutyl-2H-pyrazol-3-yl)-2-naphthalene-2-yl-acetamide
  参考文献：
  名称：

  Synthesis of aminopyrazole analogs and their evaluation as CDK inhibitors for cancer therapy

  摘要：

  We synthesized a library of aminopyrazole analogs to systematically explore the hydrophobic pocket adjacent to the hinge region and the solvent exposed region of cyclin dependent kinases. Structure-activity relationship studies identified an optimal substitution for the hydrophobic pocket and analog 24 as a potent and selective CDK2/5 inhibitor.

  DOI：

  10.1016/j.bmcl.2018.10.020

文献信息

• Pyrazole derivatives
  申请人：Sanner A. Mark

  公开号：US20050209297A1

  公开（公告）日：2005-09-22

  The invention provides compounds of formula 1 wherein R 1 , R 2 , R 3 , and R 4 are as defined, and their pharmaceutically acceptable salts. Compounds of formula 1 are indicated to have activity inhibiting cdk5, cdk2, and GSK-3. Pharmaceutical compositions and methods comprising compounds of formula 1 for treating and preventing diseases and conditions comprising abnormal cell growth, such as cancer, and neurodegenerative diseases and conditions and those affected by dopamine neurotransmission. Also described are pharmaceutical compositions and methods comprising compounds of formula 1 for treating male fertility and sperm motility; diabetes mellitus; impaired glucose tolerance; metabolic syndrome or syndrome X; polycystic ovary syndrome; adipogenesis and obesity; myogenesis and frailty, for example age-related decline in physical performance; acute sarcopenia, for example muscle atrophy and/or cachexia associated with burns, bed rest, limb immobilization, or major thoracic, abdominal, and/or orthopedic surgery; sepsis; hair loss, hair thinning, and balding; and immunodeficiency.

  本发明提供了式1的化合物，其中R1、R2、R3和R4如定义所述，以及其药物可接受的盐。式1的化合物被指示具有抑制cdk5、cdk2和GSK-3的活性。本发明还描述了包括式1的化合物的药物组合物和方法，用于治疗和预防包括异常细胞生长的疾病和病况，如癌症和神经退行性疾病和病况以及受多巴胺神经递质影响的疾病和病况。还描述了包括式1的化合物的药物组合物和方法，用于治疗男性生育能力和精子运动能力；糖尿病；糖耐量受损；代谢综合征或综合征X；多囊卵巢综合征；脂肪生成和肥胖症；肌肉生成和衰弱，例如与年龄相关的身体表现下降；急性肌肉萎缩，例如与烧伤、卧床休息、肢体固定或重要胸部、腹部和/或骨科手术相关的肌肉萎缩和/或消瘦；败血症；脱发、头发变薄和秃发；免疫缺陷症。