4-(1-methyl-1H-pyrazol-5-yl)benzoic acid | 1189977-24-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: 4-(1-methyl-1H-pyrazol-5-yl)benzoic acid
• 英文别名: 4-(2-Methyl-2H-pyrazol-3-yl)-benzoic acid；4-(2-methylpyrazol-3-yl)benzoic acid
• CAS: 1189977-24-9
• 化学式: C₁₁H₁₀N₂O₂
• 分子量: 202.213
• InChiKey: YJGQJSCTEQJHMT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  55.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(1-methyl-1H-pyrazol-5-yl)benzoic acid 在 盐酸 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 7.0h， 生成 N-((3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl)-4-(1-methyl-1H-pyrazol-5-yl)benzamide (2R,3R)-2,3-dihydroxysuccinate
  参考文献：
  名称：

  Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design

  摘要：

  A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, Al2, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure activity relationship of compound Al2, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Aktl and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.

  DOI：

  10.1021/acs.jmedchem.9b00891
• 作为产物：
  描述：

  对溴苯甲酸甲酯 在 potassium phosphate 、 四(三苯基膦)钯 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 生成 4-(1-methyl-1H-pyrazol-5-yl)benzoic acid
  参考文献：
  名称：

  Discovery of 3,4,6-Trisubstituted Piperidine Derivatives as Orally Active, Low hERG Blocking Akt Inhibitors via Conformational Restriction and Structure-Based Design

  摘要：

  A series of 3,4-disubstituted piperidine derivatives were obtained based on a conformational restriction strategy and a lead compound, Al2, that exhibited potent in vitro and in vivo antitumor efficacies; however, obvious safety issues limited its further development. Thus, systematic exploration of the structure activity relationship of compound Al2, involving the phenyl group, hinge-linkage, and piperidine moiety, led to the discovery of the superior 3,4,6-trisubstituted piperidine derivative E22. E22 showed increased potency in Aktl and cancer cell inhibition, remarkably reduced human ether-a-go-go-related gene blockage, and significantly improved safety profiles. Compound E22 also exhibited good kinase selectivity, had a good pharmacokinetic profile, and displayed very potent in vivo antitumor efficacy, with over 90% tumor growth inhibition in the SKOV3 xenograft model. Further mechanistic studies were conducted to demonstrate that compound E22 could significantly inhibit the phosphorylation of proteins downstream of Akt kinase in cells and tumor tissue from the xenograft model.

  DOI：

  10.1021/acs.jmedchem.9b00891

文献信息

• Synthesis and evaluation of piperazinotriazoles. Discovery of a potent and orally bioavailable neurokinin-3 receptor inhibitor
  作者：Liang Ye、Yifei Yang、Chunmei Li、Jianzhao Zhang、Wenyan Wang、Mingxu Ma、Hengwei Xu、Wenjing Zhang、Fangxia Zou、Zhengping Hu、Hongbo Wang、Jingwei Tian

  DOI：10.1016/j.ejmech.2023.115486

  日期：2023.9

  target compound exhibited promising inhibitory activity against NK3R (IC = 430.60 nM) with excellent membrane permeability (Papp, A-B = 37.6 × 10 cm/s, ER < 1) and oral bioavailability (F% = 93.6%). Our in vivo studies demonstrated that was orally active, efficacious, and well-tolerated in ovariectomy (OVX) model to suppress blood luteinizing hormone levels, which suggests that 16x is a viable lead compound

  神经激肽-3 受体 (NK3R) 是识别神经激肽的三种受体之一。使用口服 NK3R 拮抗剂药理阻断神经激肽 B (NKB) 信号传导可以显着改善潮热症状，且与任何激素效应无关，这一发现强烈表明 NK3R 是一个可行的药物靶点，并且针对该受体的药物可能是新型药物疗法。目前还没有 NK3R 配体被批准用于治疗人类疾病。在此，我们设计并合成了一系列新型咪唑哌嗪衍生物（）并进行分子对接验证了该设计，其中目标化合物对NK3R表现出良好的抑制活性（IC = 430.60 nM），并具有优异的膜通透性（Papp，AB = 37.6） × 10 cm/s，ER < 1) 和口服生物利用度 (F% = 93.6%)。我们的体内研究表明，16x 在卵巢切除 (OVX) 模型中具有口服活性、有效且耐受性良好，可抑制血液黄体生成激素水平，这表明 16x 是一种可行的先导化合物，可用于进一步优化和开发。
• Phenotypic Screening-Based Identification of 3,4-Disubstituted Piperidine Derivatives as Macrophage M2 Polarization Modulators: An Opportunity for Treating Multiple Sclerosis
  作者：Qinjie Weng、Jinxin Che、Zhikang Zhang、Jiahuan Zheng、Wenhu Zhan、Sendong Lin、Tian Tian、Jincheng Wang、Renhua Gai、Yongzhou Hu、Bo Yang、Qiaojun He、Xiaowu Dong

  DOI：10.1021/acs.jmedchem.8b01635

  日期：2019.4.11

  Multiple sclerosis (MS) is a disease of the autoimmune-mediated disorder in the central nervous system, for which no effective therapeutic agent is currently available. The regulation of macrophage polarization toward M2 is a general benefit for treating MS. The gene biomarker-based phenotypic screening approach was developed, and 3,4-disubstituted piperidine derivative S-28 was identified as a lead compound modulating macrophage M2 polarization. Further SAR studies resulted in the discovery of the most potent modulator D11 that showed good oral bioavailability and significant in vivo therapeutic effects. Mechanistic studies demonstrated that the M2 polarization macrophages modulated by D11 mainly functioned through inhibiting the proliferation of T-cells and activating the phosphorylation of Stat3 and Akt. Therefore, the gene biomarker-based phenotypic screening was demonstrated as a promising tool for the discovery of novel macrophage M2 polarization modulators. Compound D11 may serve as a promising starting point for the development of therapeutics to treat MS.