6-(1-methyl-1H-pyrazol-5-yl)nicotinic acid | 1211530-17-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 6-(1-methyl-1H-pyrazol-5-yl)nicotinic acid
• 英文别名: 6-(1-Methyl-1H-pyrazol-5-yl)-3-pyridinecarboxylic acid；6-(2-methylpyrazol-3-yl)pyridine-3-carboxylic acid
• CAS: 1211530-17-4
• 化学式: C₁₀H₉N₃O₂
• 分子量: 203.2
• InChiKey: FASWVGYIGILDFF-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.4
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  68
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  tert-butyl (3S,4S)-3-amino-4-(3,4-difluorophenyl)piperidine-1-carboxylate 、 6-(1-methyl-1H-pyrazol-5-yl)nicotinic acid 在 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 、 盐酸 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 11.0h， 以47%的产率得到N-((3S,4S)-4-(3,4-difluorophenyl)piperidin-3-yl)-6-(1-methyl-1H-pyrazol-5-yl)nicotinamide hydrochloride
  参考文献：
  名称：

  Phenotypic Screening-Based Identification of 3,4-Disubstituted Piperidine Derivatives as Macrophage M2 Polarization Modulators: An Opportunity for Treating Multiple Sclerosis

  摘要：

  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.

  DOI：

  10.1021/acs.jmedchem.8b01635
• 作为产物：
  描述：

  6-溴烟酸甲酯 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 6-(1-methyl-1H-pyrazol-5-yl)nicotinic 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