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(S)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-[1,1′-biphenyl]-4-carboxamide

中文名称
——
中文别名
——
英文名称
(S)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-[1,1′-biphenyl]-4-carboxamide
英文别名
(S)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-[1,1'-biphenyl]-4-carboxamide;N-[(2S)-3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl]-4-phenylbenzamide
(S)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-[1,1′-biphenyl]-4-carboxamide化学式
CAS
——
化学式
C29H24N4O2
mdl
——
分子量
460.535
InChiKey
LLSJICAHGPWSLF-MHZLTWQESA-N
BEILSTEIN
——
EINECS
——
  • 物化性质
  • 计算性质
  • ADMET
  • 安全信息
  • SDS
  • 制备方法与用途
  • 上下游信息
  • 反应信息
  • 文献信息
  • 表征谱图
  • 同类化合物
  • 相关功能分类
  • 相关结构分类

计算性质

  • 辛醇/水分配系数(LogP):
    4.6
  • 重原子数:
    35
  • 可旋转键数:
    7
  • 环数:
    5.0
  • sp3杂化的碳原子比例:
    0.07
  • 拓扑面积:
    86.9
  • 氢给体数:
    3
  • 氢受体数:
    3

上下游信息

  • 上游原料
    中文名称 英文名称 CAS号 化学式 分子量

反应信息

  • 作为产物:
    描述:
    4-氨基吡啶盐酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 1-羟基苯并三唑三乙胺 作用下, 以 1,4-二氧六环二氯甲烷 为溶剂, 反应 14.25h, 生成 (S)-N-(3-(1H-indol-3-yl)-1-oxo-1-(pyridin-4-ylamino)propan-2-yl)-[1,1′-biphenyl]-4-carboxamide
    参考文献:
    名称:
    Rational Development of 4-Aminopyridyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 as Anti-Chagas Agents
    摘要:
    A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (K-D <= 42 nM; EC50 = 0.65 mu M), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYR51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 mu M). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
    DOI:
    10.1021/jm401067s
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文献信息

  • [EN] NOVEL AGENTS TARGETING CYP51<br/>[FR] NOUVEAUX AGENTS CIBLANT CYP51
    申请人:SCRIPPS RESEARCH INST
    公开号:WO2015048306A1
    公开(公告)日:2015-04-02
    The invention provides inhibitors of a sterol C14-demethylase, a new series of 4- aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) developed using structure-based drug design as well as structure -property relationship (SPR) analyses. The screening hit starting point, LP 10 (KD < 42 nM; EC50 of 0.65 μΜ), has been optimized to give the potential leads that have low nanomolar binding affinity to TcCYP51 and significant activity against T. cruzi amastigotes cultured in human myoblasts. Many of the optimized compounds have improved microsome stability, and most are selective against the T. cruzi CYP51 relative to human CYPs 1A2, 2D6 and 3A4 (<50% inhibition at 1 μΜ). A rationale for the improvement of microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of several compounds of the invention with the T. brucei CYP51 (TbCYP51) ortholog has been characterized by x-ray structure analysis. Orally active compounds and their cyclodextrin complexes have been shown to be effective against Chagas-infected mice.
    该发明提供了一种甾醇C14-去甲基酶的抑制剂,这是一种新系列基于4-氨基吡啶的首选抑制剂,通过基于结构的药物设计以及结构-性质关系(SPR)分析来瞄准Trypanosoma cruzi CYP51(TcCYP51)而开发的。筛选起始点LP 10(KD < 42 nM;EC50为0.65 μΜ)已经经过优化,产生了具有低纳摩尔级别结合亲和力和对在人类肌细胞培养的T. cruzi游离体的显著活性的潜在首选抑制剂。许多经过优化的化合物具有改善的微粒体稳定性,大多数相对于人类CYPs 1A2、2D6和3A4对T. cruzi CYP51具有选择性(在1 μΜ下<50%的抑制)。提出了改善微粒体稳定性和抑制剂对人类代谢CYP酶的选择性的理由。此外,通过X射线结构分析表征了该发明的几种化合物与T. brucei CYP51(TbCYP51)同源物的结合方式。口服活性化合物及其环糊精复合物已被证明对克氏病感染的小鼠有效。
  • Rational Development of 4-Aminopyridyl-Based Inhibitors Targeting Trypanosoma cruzi CYP51 as Anti-Chagas Agents
    作者:Jun Yong Choi、Claudia M. Calvet、Shamila S. Gunatilleke、Claudia Ruiz、Michael D. Cameron、James H. McKerrow、Larissa M. Podust、William R. Roush
    DOI:10.1021/jm401067s
    日期:2013.10.10
    A new series of 4-aminopyridyl-based lead inhibitors targeting Trypanosoma cruzi CYP51 (TcCYP51) has been developed using structure-based drug design as well as structure-property relationship (SPR) analyses. The screening hit starting point, LP10 (K-D <= 42 nM; EC50 = 0.65 mu M), has been optimized to give the potential leads 14t, 27i, 27q, 27r, and 27t, which have low-nanomolar binding affinity to TcCYR51 and significant activity against T. cruzi amastigotes cultured in human myoblasts (EC50 = 14-18 nM for 27i and 27r). Many of the optimized compounds have improved microsome stability, and most are selective against human CYPs 1A2, 2D6, and 3A4 (<50% inhibition at 1 mu M). A rationale for the improvement in microsome stability and selectivity of inhibitors against human metabolic CYP enzymes is presented. In addition, the binding mode of 14t with the Trypanosoma brucei CYP51 (TbCYP51) orthologue has been characterized by X-ray structure analysis.
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