4-(Piperidin-2-yl)pyridine hydrochloride | 143924-49-6

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 4-(Piperidin-2-yl)pyridine hydrochloride
• 英文别名: 4-piperidin-2-ylpyridine;hydrochloride
• CAS: 143924-49-6
• 化学式: C₁₀H₁₄N₂*ClH
• 分子量: 198.695
• InChiKey: KSRKXXXJJOFHIY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.32
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  24.9
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(benzo[d][1,3]dioxole-5-carboxamido)benzene-1-sulfonyl chloride 、 4-(Piperidin-2-yl)pyridine hydrochloride 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 15.0h， 以15 mg的产率得到
  参考文献：
  名称：

  A novel inhibitor of inducible NOS dimerization protects against cytokine-induced rat beta cell dysfunction

  摘要：

  Background and PurposeBeta cell apoptosis is a major feature of type 1 diabetes, and pro‐inflammatory cytokines are key drivers of the deterioration of beta cell mass through induction of apoptosis. Mitochondrial stress plays a critical role in mediating apoptosis by releasing cytochrome C into the cytoplasm, directly activating caspase‐9 and its downstream signalling cascade. We aimed to identify new compounds that protect beta cells from cytokine‐induced activation of the intrinsic (mitochondrial) pathway of apoptosis.Experimental ApproachDiabetogenic media, composed of IL‐1β, IFN‐γ and high glucose, were used to induce mitochondrial stress in rat insulin‐producing INS1E cells, and a high‐content image‐based screen of small molecule modulators of Casp9 pathway was performed.Key ResultsA novel small molecule, ATV399, was identified from a high‐content image‐based screen for compounds that inhibit cleaved caspase‐9 activation and subsequent beta cell apoptosis induced by a combination of IL‐1β, IFN‐γ and high glucose, which together mimic the pathogenic diabetic milieu. Through medicinal chemistry optimization, potency was markedly improved (6–30 fold), with reduced inhibitory effects on CYP3A4. Improved analogues, such as CAT639, improved beta cell viability and insulin secretion in cytokine‐treated rat insulin‐producing INS1E cells and primary dispersed islet cells. Mechanistically, CAT639 reduced the production of NO by allosterically inhibiting dimerization of inducible NOS (iNOS) without affecting its mRNA levels.Conclusion and ImplicationsTaken together, these studies demonstrate a successful phenotypic screening campaign resulting in identification of an inhibitor of iNOS dimerization that protects beta cell viability and function through modulation of mitochondrial stress induced by cytokines.

  DOI：

  10.1111/bph.14388
• 作为产物：
  描述：

  1-Boc-哌啶 在 盐酸 、 四甲基乙二胺 、 仲丁基锂 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 23.0h， 生成 4-(Piperidin-2-yl)pyridine hydrochloride
  参考文献：
  名称：

  A novel inhibitor of inducible NOS dimerization protects against cytokine-induced rat beta cell dysfunction

  摘要：

  Background and PurposeBeta cell apoptosis is a major feature of type 1 diabetes, and pro‐inflammatory cytokines are key drivers of the deterioration of beta cell mass through induction of apoptosis. Mitochondrial stress plays a critical role in mediating apoptosis by releasing cytochrome C into the cytoplasm, directly activating caspase‐9 and its downstream signalling cascade. We aimed to identify new compounds that protect beta cells from cytokine‐induced activation of the intrinsic (mitochondrial) pathway of apoptosis.Experimental ApproachDiabetogenic media, composed of IL‐1β, IFN‐γ and high glucose, were used to induce mitochondrial stress in rat insulin‐producing INS1E cells, and a high‐content image‐based screen of small molecule modulators of Casp9 pathway was performed.Key ResultsA novel small molecule, ATV399, was identified from a high‐content image‐based screen for compounds that inhibit cleaved caspase‐9 activation and subsequent beta cell apoptosis induced by a combination of IL‐1β, IFN‐γ and high glucose, which together mimic the pathogenic diabetic milieu. Through medicinal chemistry optimization, potency was markedly improved (6–30 fold), with reduced inhibitory effects on CYP3A4. Improved analogues, such as CAT639, improved beta cell viability and insulin secretion in cytokine‐treated rat insulin‐producing INS1E cells and primary dispersed islet cells. Mechanistically, CAT639 reduced the production of NO by allosterically inhibiting dimerization of inducible NOS (iNOS) without affecting its mRNA levels.Conclusion and ImplicationsTaken together, these studies demonstrate a successful phenotypic screening campaign resulting in identification of an inhibitor of iNOS dimerization that protects beta cell viability and function through modulation of mitochondrial stress induced by cytokines.

  DOI：

  10.1111/bph.14388

文献信息

• A novel inhibitor of inducible NOS dimerization protects against cytokine-induced rat beta cell dysfunction
  作者：Linlin Zhong、Tuan Tran、Tyler D Baguley、Sang Jun Lee、Adam Henke、Andrew To、Sijia Li、Shan Yu、Fabio A Grieco、Jason Roland、Peter G Schultz、Decio L Eizirik、Nikki Rogers、Arnab K Chartterjee、Matthew S Tremblay、Weijun Shen

  DOI：10.1111/bph.14388

  日期：2018.9

  Background and PurposeBeta cell apoptosis is a major feature of type 1 diabetes, and pro‐inflammatory cytokines are key drivers of the deterioration of beta cell mass through induction of apoptosis. Mitochondrial stress plays a critical role in mediating apoptosis by releasing cytochrome C into the cytoplasm, directly activating caspase‐9 and its downstream signalling cascade. We aimed to identify new compounds that protect beta cells from cytokine‐induced activation of the intrinsic (mitochondrial) pathway of apoptosis.Experimental ApproachDiabetogenic media, composed of IL‐1β, IFN‐γ and high glucose, were used to induce mitochondrial stress in rat insulin‐producing INS1E cells, and a high‐content image‐based screen of small molecule modulators of Casp9 pathway was performed.Key ResultsA novel small molecule, ATV399, was identified from a high‐content image‐based screen for compounds that inhibit cleaved caspase‐9 activation and subsequent beta cell apoptosis induced by a combination of IL‐1β, IFN‐γ and high glucose, which together mimic the pathogenic diabetic milieu. Through medicinal chemistry optimization, potency was markedly improved (6–30 fold), with reduced inhibitory effects on CYP3A4. Improved analogues, such as CAT639, improved beta cell viability and insulin secretion in cytokine‐treated rat insulin‐producing INS1E cells and primary dispersed islet cells. Mechanistically, CAT639 reduced the production of NO by allosterically inhibiting dimerization of inducible NOS (iNOS) without affecting its mRNA levels.Conclusion and ImplicationsTaken together, these studies demonstrate a successful phenotypic screening campaign resulting in identification of an inhibitor of iNOS dimerization that protects beta cell viability and function through modulation of mitochondrial stress induced by cytokines.