3-(bromomethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole | 913624-95-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 3-(bromomethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole
• 英文别名: 3-(Bromomethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazole
• CAS: 913624-95-0
• 化学式: C₁₇H₁₂BrCl₃N₂
• 分子量: 430.559
• InChiKey: GXDDDLWGDDOCJZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  17.8
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  3-(bromomethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole 在 氯化亚砜 、 硫酸 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.5h， 生成 ethyl 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)acetate
  参考文献：
  名称：

  1-(5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-基)-2-吗啉代乙烷-1,2-二酮类似物的合成及其抑制活性在脂多糖诱导的 BV2 细胞中具有降低的细胞毒性

  摘要：

  合成了一系列利莫那班类似物，其中N-氨基哌啶部分被各种胺和一个额外的羰基取代，并在脂多糖 (LPS) 诱导的 BV2 小胶质细胞中评估了它们对一氧化氮 (NO) 产生的抑制作用。在合成的化合物中，吗啉类似物7y (IC 50 = 4.71 ± 0.11 μM) 显示出比利莫那班 (IC 50 = 16.17 ± 0.56 μM) 显着更高的抑制活性 ，并且剂量依赖性地抑制 NO 产生而没有细胞毒性。此外，7y抑制 BV2 细胞中 iNOS、COX-2 和促炎细胞因子的表达，并减弱 LPS 诱导的核因子-κB (NF-κB) 和 ERK MAPK 磷酸化的激活。这些结果表明7y通过ERK途径在BV2细胞中发挥抗炎作用，可用于神经炎症性疾病的预防和治疗。

  DOI：

  10.1016/j.bmcl.2022.129061
• 作为产物：
  描述：

  2,4-二氯苯肼盐酸盐 在 lithium aluminium tetrahydride 、 三溴化磷 、 溶剂黄146 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 苯 为溶剂， 反应 45.25h， 生成 3-(bromomethyl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole
  参考文献：
  名称：

  Design, synthesis and biological evaluation of CB1 cannabinoid receptor ligands derived from the 1,5-diarylpyrazole scaffold

  摘要：

  The CB1 receptor belongs to the G-protein-coupled receptor superfamily. CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In this study, we report the synthesis and in vitro binding affinity assay of some 1,5-diarylpyrazole scaffold compounds. The binding results showed that some of the target compounds had an excellent potency toward the CB1 receptor with IC(50) values lying at the nanomole level.

  DOI：

  10.3109/14756366.2010.491794

文献信息

• Biarylpyrazole Inverse Agonists at the Cannabinoid CB1 Receptor:  Importance of the C-3 Carboxamide Oxygen/Lysine3.28(192) Interaction
  作者：Dow Hurst、Uju Umejiego、Diane Lynch、Herbert Seltzman、Steven Hyatt、Michael Roche、Sean McAllister、Daniel Fleischer、Ankur Kapur、Mary Abood、Shanping Shi、Jannie Jones、Deborah Lewis、Patricia Reggio

  DOI：10.1021/jm060446b

  日期：2006.10.1

  values versus [3H]CP55,940 reported here. In calcium channel assays, all analogues with carboxamide oxygens (1, 3, and 4) were found to be inverse agonists, whereas those that lacked this group (2, 5, and 6) were found to be neutral antagonists. Taken together, these results support the hypothesis that it is the carboxamide oxygen of the C-3 substituent of 1 that engages in a hydrogen bond with K3

  已显示联芳基吡唑，N-（哌啶-1-基）-5-（4-氯苯基）-1-（2,4-二氯苯基）-4-甲基-1H-吡唑-3-甲酰胺（SR141716; 1）在大麻素CB1受体上起反向激动剂/拮抗剂的作用。我们之前的突变周期研究表明，K3.28（192）与野生型（WT）CB1中1的C-3取代基直接相互作用。（1）但是，这些结果并未确定1的C-3取代基与K3.28（192）氢键，羧酰胺氧或哌啶氮有关。此外，我们先前的5-（4-氯苯基）-3-[（E）-2-环己基乙烯基] -1-（2,4-二氯苯基）-4-甲基-1H-吡唑（VCHSR; 2 ）（1的类似物，其C-3取代基缺乏氢键能力）表明该化合物可作为中性拮抗剂，（1）这些结果表明联芳基吡唑与CB1处的K3.28（192）相互作用与反向激动作用之间存在一定的关系，但结果与1相反。单对化合物（1和2）。本文介绍的工作旨在测试从我们的建模和突变周期结果得出的两个假
• <i>N</i>-(Piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1<i>H</i>-pyrazole-3-carboxamide (SR141716A) Interaction with LYS 3.28(192) Is Crucial for Its Inverse Agonism at the Cannabinoid CB1 Receptor
  作者：Dow P. Hurst、Diane L. Lynch、Judy Barnett-Norris、Stephen M. Hyatt、Herbert H. Seltzman、Miao Zhong、Zhao-Hui Song、Jingjiang Nie、Deborah Lewis、Patricia H. Reggio

  DOI：10.1124/mol.62.6.1274

  日期：2002.12.1

  In superior cervical ganglion neurons, N -(piperidiny-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole-3-carboxamide (SR141716A) competitively antagonizes the Ca2+ current effect of the cannabinoid (CB) agonist ( R )-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl)pyrrolo[1,2,3- de ]-1,4-benzoxazin-6-yl]-1-naphthalenylmethanone (WIN55212-2), and behaves as an inverse agonist by producing opposite current effects when applied alone. In contrast, in neurons expressing CB1 with a K→A mutation at residue 3.28(192) (i.e., K3.28A), SR141716A competitively antagonizes the effects of WIN55212-2, but behaves as a neutral antagonist by producing no current effects itself. Receptor modeling studies suggested that in the CB1 inactive (R) state, SR1417A16A stabilizes transmembrane helix 6 in its inactive conformation via aromatic stacking with F3.36/W6.48. In this binding site, SR141716A would exhibit higher affinity for CB1 R due to a hydrogen bond between the SR141716A C3 substituent and K3.28(192), a residue available to SR141716A only in R. To test this hypothesis, a “mutant thermodynamic cycle” was constructed that combined the evaluation of SR141716A affinity at WT CB1 and K3.28A with an evaluation of the wild-type CB1 and K3.28A affinities of an SR141716A analog, 5-(4-chlorophenyl)-3-[(E)-2-cyclohexylethenyl]-1-(2,4-dichlorophenyl)-4-methyl-1 H -pyrazole (VCHSR), that lacks hydrogen bonding potential at C3. Binding affinities suggested that K3.28 is involved in a strong interaction with SR141716A in WT CB1, but does not interact with VCHSR. Thermodynamic cycle calculations indicated that a direct interaction occurs between the C3 substituent of SR141716A and K3.28 in WT CB1. Consistent with these results, VCHSR acted as a neutral antagonist at WT CB1. These results support the hypothesis that hydrogen bonding of the SR141716A C3 substituent with K3.28 is responsible for its higher affinity for the inactive R state, leading to its inverse agonism.

  在颈上神经节神经元中，N-(哌啶-1-基)-5-(4-氯苯基)-1-(2,4-二氯苯基)-4-甲基-1H-吡唑-3-甲酰胺(SR141716A)竞争性拮抗大麻素 (CB) 激动剂 ( R )-(+)-[2,3-二氢-5-甲基-3-(4-吗啉基甲基)吡咯并[1,2,3- de ]-1 的 Ca2+ 电流效应,4-苯并恶嗪-6-基]-1-萘基甲酮 (WIN55212-2)，单独使用时可产生相反的电流效应，充当反向激动剂。相反，在表达残基 3.28(192) 处具有 K→A 突变（即 K3.28A）的 CB1 的神经元中，SR141716A 竞争性拮抗 WIN55212-2 的作用，但本身不产生电流作用，从而表现为中性拮抗剂。受体建模研究表明，在 CB1 非活性 (R) 状态下，SR1417A16A 通过与 F3.36/W6.48 的芳香堆积，将跨膜螺旋 6 稳定在非活性构象。在这个结合位点，由于 SR141716A C3 取代基和 K3.28(192) 之间存在氢键，SR141716A 对 CB1 R 表现出更高的亲和力，K3.28(192) 是 SR141716A 仅在 R 中可用的残基。为了检验这一假设，“突变热力学循环” ”的构建结合了对 WT CB1 和 K3.28A 的 SR141716A 亲和力的评估与对 SR141716A 类似物 5-(4-氯苯基)-3-[(E) 的野生型 CB1 和 K3.28A 亲和力的评估-2-环己基乙烯基]-1-(2,4-二氯苯基)-4-甲基-1H-吡唑(VCHSR)，在C3处缺乏氢键键合潜力。结合亲和力表明 K3.28 参与与 WT CB1 中的 SR141716A 的强相互作用，但不与 VCHSR 相互作用。热力学循环计算表明，SR141716A 的 C3 取代基与 WT CB1 中的 K3.28 之间发生直接相互作用。与这些结果一致，VCHSR 充当 WT CB1 的中性拮抗剂。这些结果支持这样的假设：SR141716A C3 取代基与 K3.28 的氢键导致其对非活性 R 态具有更高的亲和力，从而导致其反向激动作用。
• 2-(5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-N-(2-hydroxyethyl)-2-oxoacetamide (CDMPO) has anti-inflammatory properties in microglial cells and prevents neuronal and behavioral deficits in MPTP mouse model of Parkinson's disease
  作者：Byungwook Kim、Ju-Young Park、Duk-Yeon Cho、Hyun Myung Ko、Sung-Hwa Yoon、Dong-Kug Choi

  DOI：10.1016/j.neuropharm.2019.107928

  日期：2020.4

  Parkinson's disease (PD) is characterized by the selective loss of nigrostriatal dopamine neurons associated with microglial activation. Inhibition of the inflammatory response elicited by activated microglia could be an effective strategy to alleviate the progression of PD. Here, we synthesized 2-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-N-(2-hydroxyethyl)-2-oxoacetamide (CDMPO) and studied its protective anti-inflammatory mechanisms following lipopolysaccharide (LPS)-induced neuroinflammation in vitro and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity in vivo. CDMPO and its parent compound, rimonabant, significantly attenuated nitric oxide (NO) production in LPS-stimulated primary microglia and BV2 cells. Furthermore, CDMPO significantly inhibited the release of proinflammatory cytokines and prostaglandin E2 (PGE(2)) by activated BV2 cells, also suppressed expression of inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). Mechanistically, CDMPO attenuated LPS-induced activation of nuclear factor-kappa B (NF-kappa B), inhibitor of kappa B alpha (I kappa B alpha), and p38 phosphorylation in BV2 cells. MPTP intoxication of mice results in glial activation, tyrosine hydroxylase (TH) depletion, and significant behavioral deficits. Prophylactic treatment with CDMPO decreased proinflammatory molecules via NF-kappa B and p38 mitogen-activated protein kinase signaling, resulting in protection of dopaminergic neurons and improved behavioral impairments. These results suggest that CDMPO is a promising neuroprotective agent for the prevention and treatment of microglia-mediated neuroinflammatory conditions and may be useful for behavioral improvement in PD phenotype.
• Design, synthesis and biological evaluation of CB1 cannabinoid receptor ligands derived from the 1,5-diarylpyrazole scaffold
  作者：GuoGang Tu、Fang Xiong、HuiMing Huang、BinHai Kuang、ShaoHua Li

  DOI：10.3109/14756366.2010.491794

  日期：2011.4.1

  The CB1 receptor belongs to the G-protein-coupled receptor superfamily. CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In this study, we report the synthesis and in vitro binding affinity assay of some 1,5-diarylpyrazole scaffold compounds. The binding results showed that some of the target compounds had an excellent potency toward the CB1 receptor with IC(50) values lying at the nanomole level.
• Synthesis of 1-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazol-3-yl)-2-morpholinoethane-1,2-dione analogues and their inhibitory activities with reduced cytotoxicity in lipopolysaccharide-induced BV2 cells
  作者：Sung-Hwa Yoon、Duk-Yeon Cho、Jun-Hyuk Han、Dong-Kug Choi、Eunha Kim、Ju-Young Park

  DOI：10.1016/j.bmcl.2022.129061

  日期：2023.1

  of rimonabant analogues, where the N-aminopiperidine moiety was replaced by various amines and an additional carbonyl group, were synthesized and their inhibition of nitric oxide (NO) production was evaluated in lipopolysaccharide (LPS)-induced BV2 microglial cells. Among the synthesized compounds, the morpholine analogue 7y (IC50 = 4.71 ± 0.11 μM) showed significantly higher inhibitory activity than

  合成了一系列利莫那班类似物，其中N-氨基哌啶部分被各种胺和一个额外的羰基取代，并在脂多糖 (LPS) 诱导的 BV2 小胶质细胞中评估了它们对一氧化氮 (NO) 产生的抑制作用。在合成的化合物中，吗啉类似物7y (IC 50 = 4.71 ± 0.11 μM) 显示出比利莫那班 (IC 50 = 16.17 ± 0.56 μM) 显着更高的抑制活性 ，并且剂量依赖性地抑制 NO 产生而没有细胞毒性。此外，7y抑制 BV2 细胞中 iNOS、COX-2 和促炎细胞因子的表达，并减弱 LPS 诱导的核因子-κB (NF-κB) 和 ERK MAPK 磷酸化的激活。这些结果表明7y通过ERK途径在BV2细胞中发挥抗炎作用，可用于神经炎症性疾病的预防和治疗。