N-benzyl-6-(4-(2-(trifluoromethyl)benzoyl)piperazin-1-yl)-pyridazine-3-carboxamide | 1417790-11-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-benzyl-6-(4-(2-(trifluoromethyl)benzoyl)piperazin-1-yl)-pyridazine-3-carboxamide
• 英文别名: N-benzyl-6-[4-[2-(trifluoromethyl)benzoyl]piperazin-1-yl]pyridazine-3-carboxamide
• CAS: 1417790-11-4
• 化学式: C₂₄H₂₂F₃N₅O₂
• 分子量: 469.466
• InChiKey: CKIBNNYWZAXTRH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  34
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  78.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  2-三氟甲基苯甲酰氯 在 氯化亚砜 、 lithium hydroxide monohydrate 、 四丁基碘化铵 、 potassium carbonate 、 三乙胺 、 N,N-二异丙基乙胺 、 N,N-二甲基甲酰胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 氯仿 、 水 为溶剂， 反应 72.0h， 生成 N-benzyl-6-(4-(2-(trifluoromethyl)benzoyl)piperazin-1-yl)-pyridazine-3-carboxamide
  参考文献：
  名称：

  Discovery of Piperazin-1-ylpyridazine-Based Potent and Selective Stearoyl-CoA Desaturase-1 Inhibitors for the Treatment of Obesity and Metabolic Syndrome

  摘要：

  Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC50 = 14 nM and HepG2 IC50 = 12 nM) and efficacious in vivo (ED50 = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.

  DOI：

  10.1021/jm301661h

文献信息

• Piperazin-1-ylpyridazine Derivatives Are a Novel Class of Human dCTP Pyrophosphatase 1 Inhibitors
  作者：Sabin Llona-Minguez、Andreas Höglund、Artin Ghassemian、Matthieu Desroses、José Manuel Calderón-Montaño、Estefanía Burgos Morón、Nicholas C. K. Valerie、Elisee Wiita、Ingrid Almlöf、Tobias Koolmeister、André Mateus、Cindy Cazares-Körner、Kumar Sanjiv、Evert Homan、Olga Loseva、Pawel Baranczewski、Masoud Darabi、Amir Mehdizadeh、Shabnam Fayezi、Ann-Sofie Jemth、Ulrika Warpman Berglund、Kristmundur Sigmundsson、Thomas Lundbäck、Annika Jenmalm Jensen、Per Artursson、Martin Scobie、Thomas Helleday

  DOI：10.1021/acs.jmedchem.7b00182

  日期：2017.5.25

  The dCTP pyrophosphatase 1 (dCTPase) is a nucleotide pool “housekeeping” enzyme responsible for the catabolism of canonical and noncanonical nucleoside triphosphates (dNTPs) and has been associated with cancer progression and cancer cell stemness. We have identified a series of piperazin-1-ylpyridazines as a new class of potent dCTPase inhibitors. Lead compounds increase dCTPase thermal and protease

  dCTP焦磷酸酶1（dCTPase）是一种核苷酸库“管家”酶，负责规范和非规范的核苷三磷酸（dNTPs）的分解代谢，并与癌症进展和癌细胞干细胞相关。我们已经鉴定出一系列哌嗪-1-基哒嗪类作为一类新的有效的dCTPase抑制剂。铅化合物可提高dCTPase的热稳定性和蛋白酶稳定性，对相关酶具有出色的选择性，并与胞嘧啶核苷类似物协同对抗白血病细胞。新型的dCTPase抑制剂为dCTPase酶类药物探针的开发打下了第一块石头。
• Discovery of Piperazin-1-ylpyridazine-Based Potent and Selective Stearoyl-CoA Desaturase-1 Inhibitors for the Treatment of Obesity and Metabolic Syndrome
  作者：Zaihui Zhang、Shaoyi Sun、Vishnumurthy Kodumuru、Duanjie Hou、Shifeng Liu、Nagasree Chakka、Serguei Sviridov、Sultan Chowdhury、David G. McLaren、Leslie G. Ratkay、Kuldip Khakh、Xing Cheng、Heinz W. Gschwend、Rajender Kamboj、Jianmin Fu、Michael D. Winther

  DOI：10.1021/jm301661h

  日期：2013.1.24

  Stearoyl-CoA desaturase-1 (SCD1) catalyzes de novo synthesis of monounsaturated fatty acids from saturated fatty acids. Studies have demonstrated that rodents lacking a functional SCD1 gene have an improved metabolic profile, including reduced weight gain, lower triglycerides, and improved insulin response. In this study, we discovered a series of piperazinylpyridazine-based highly potent, selective, and orally bioavailable compounds. Particularly, compound 49 (XEN103) was highly active in vitro (mSCD1 IC50 = 14 nM and HepG2 IC50 = 12 nM) and efficacious in vivo (ED50 = 0.8 mg/kg). It also demonstrated striking reduction of weight gain in a rodent model. Our findings with small-molecule SCD1 inhibitors confirm the importance of this target in metabolic regulation, describe novel models for assessing SCD1 inhibitors for efficacy and tolerability and demonstrate an opportunity to develop a novel therapy for metabolic disease.