tert-butyldimethyl((7-phenylhept-1-en-6-yn-3-yl)oxy)silane | 1276664-18-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyldimethyl((7-phenylhept-1-en-6-yn-3-yl)oxy)silane
• 英文别名: Tert-butyl-dimethyl-(7-phenylhept-1-en-6-yn-3-yloxy)silane
• CAS: 1276664-18-6
• 化学式: C₁₉H₂₈OSi
• 分子量: 300.516
• InChiKey: JFOYJVOBEHXPGZ-UHFFFAOYSA-N

物化性质

• 沸点：
  364.6±35.0 °C(Predicted)
• 密度：
  0.92±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.39
• 重原子数：
  21
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  9.2
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  tert-butyldimethyl((7-phenylhept-1-en-6-yn-3-yl)oxy)silane 在 sodium tetrahydroborate 、 dicobalt octacarbonyl 、 palladium on activated charcoal 、 溶剂黄146 作用下， 以 1,2-二氯乙烷 、 甲苯 为溶剂， 反应 20.0h， 生成 4-((tert-butyldimethylsilyl)oxy)-1-phenylhexahydropentalen-2(1H)-one
  参考文献：
  名称：

  通过添加光氧化还原缀合物开发一类新型肝受体同源物-1 (LRH-1) 激动剂。

  摘要：

  LRH-1 是一种调节脂质代谢和稳态的核受体，使其成为治疗糖尿病和非酒精性脂肪肝的有吸引力的靶点。基于我们实验室最新的配体结合结构信息，我们设计了一系列新的 LRH-1 激动剂，通过增加极性相互作用进一步与 LRH-1 结合。虽然目前该支架的合成方法在很大程度上允许对激动剂核心进行装饰，但桥头取代基的显着变化在机械上被排除。我们开发了一种新的合成方法来克服这一限制，确定桥头取代对于 LRH-1 激活是必要的，并描述了用于有效开发 LRH-1 激动剂的另一类桥头取代基。我们确定了与桥头修饰化合物结合的 LRH-1 的晶体结构，揭示了靶向配体结合袋的新区域以改变 LRH-1 靶基因表达的有希望的机会。

  DOI：

  10.1016/j.bmcl.2020.127293
• 作为产物：
  描述：

  5-苯基戊-4-炔醛 在 咪唑 、 4-二甲氨基吡啶 作用下， 以 四氢呋喃 为溶剂， 反应 18.17h， 生成 tert-butyldimethyl((7-phenylhept-1-en-6-yn-3-yl)oxy)silane
  参考文献：
  名称：

  Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)

  摘要：

  The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-y1)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.

  DOI：

  10.1021/jm1014296

文献信息

• [EN] MODULATORS OF LIVER RECEPTOR HOMOLOGUE 1 (LRH-1) AND USES<br/>[FR] MODULATEURS DE L'HOMOLOGUE 1 DU RÉCEPTEUR DU FOIE (LRH-1) ET LEURS UTILISATIONS
  申请人：UNIV EMORY

  公开号：WO2018170430A1

  公开（公告）日：2018-09-20

  This disclosure relates to modulators of liver receptor homologue 1 (LRH-1) and methods of managing disease and conditions related thereto. In certain embodiments, modulators are derivatives of hexahydropentalene. In certain embodiments, this disclosure relates to methods of treating or preventing cancer, diabetes, or cardiovascular disease by administering an effective amount of a hexahydropentalene derivative disclosed herein.

  这份披露涉及肝受体同源物1（LRH-1）的调节剂以及管理与之相关疾病和病况的方法。在某些实施例中，调节剂是六氢环戊二烯的衍生物。在某些实施例中，这份披露涉及通过给予本文披露的六氢环戊二烯衍生物的有效剂量来治疗或预防癌症、糖尿病或心血管疾病的方法。
• Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design
  作者：Suzanne G. Mays、Autumn R. Flynn、Jeffery L. Cornelison、C. Denise Okafor、Hongtao Wang、Guohui Wang、Xiangsheng Huang、Heather N. Donaldson、Elizabeth J. Millings、Rohini Polavarapu、David D. Moore、John W. Calvert、Nathan T. Jui、Eric A. Ortlund

  DOI：10.1021/acs.jmedchem.9b00753

  日期：2019.12.26

  inflammatory bowel diseases (IBD). Discovery of LRH-1 modulators has been difficult, in part due to the tendency for synthetic compounds to bind unpredictably within the lipophilic binding pocket. Using a structure-guided approach, we exploited a newly discovered polar interaction to lock agonists in a consistent orientation. This enabled the discovery of the first low nanomolar LRH-1 agonist, one hundred

  作为新陈代谢和炎症的关键调节因子，孤儿核激素受体肝受体同系物 1 (LRH-1) 有潜力成为糖尿病、非酒精性脂肪肝和炎症性肠病 (IBD) 的治疗靶点。LRH-1 调节剂的发现一直很困难，部分原因是合成化合物倾向于在亲脂性结合口袋内不可预测地结合。使用结构引导方法，我们利用新发现的极性相互作用将激动剂锁定在一致的方向。这使得第一个低纳摩尔 LRH-1 激动剂的发现成为可能，比以前最好的调节剂强一百倍。我们阐明了一种新的作用机制，该机制依赖于 LRH-1 结合口袋深处的特定极性相互作用。在 IBD 的类器官模型中，新的激动剂增加了 LRH-1 控制的类固醇生成基因的表达，并促进了抗炎基因表达的变化。这些研究构成了开发具有潜在临床效用的 LRH-1 调节剂的重大进展。
• Development of a Versatile and Sensitive Direct Ligand Binding Assay for Human NR5A Nuclear Receptors
  作者：Emma H. D’Agostino、Autumn R. Flynn、Jeffery L. Cornelison、Suzanne G. Mays、Anamika Patel、Nathan T. Jui、Eric A. Ortlund

  DOI：10.1021/acsmedchemlett.9b00442

  日期：2020.3.12

  of steroidogenesis, development, and metabolism, the nuclear receptor 5A (NR5A) subfamily members steroidogenic factor 1 (SF-1) and liver receptor homologue 1 (LRH-1) are important pharmacological targets for cancers and metabolic diseases. Evaluation of small molecule modulators and candidate endogenous ligands for these orphan receptors has been hindered by the lack of accessible, robust direct-binding

  作为类固醇生成，发育和代谢的调节剂，核受体5A（NR5A）亚家族成员类固醇生成因子1（SF-1）和肝受体同源物1（LRH-1）是癌症和代谢性疾病的重要药理学靶标。对于这些孤儿受体的小分子调节剂和候选内源性配体的评估由于缺乏可访问的，稳健的直接结合测定法而受到阻碍。在这里，我们利用新的NR5A激动剂（6N）的功效，通过将6N与荧光素（FAM）结合来创建用于荧光偏振竞争测定的高亲和力探针。6N-FAM探针紧密结合NR5A受体，并检测合成和磷脂配体的直接结合。对于25种LRH-1激动剂，亲和力可预测细胞活化试验的效力，证明了这种方法在药物发现中的潜力。此外，磷脂二月桂酰磷脂酰胆碱和磷脂酰肌醇（4,5）磷酸具有高亲和力结合，证明该测定法对于评估人NR5A受体的候选内源性配体是可靠的。
• Development of a new class of liver receptor homolog-1 (LRH-1) agonists by photoredox conjugate addition
  作者：Jeffery L. Cornelison、Michael L. Cato、Alyssa M. Johnson、Emma H. D'Agostino、Diana Melchers、Anamika B. Patel、Suzanne G. Mays、René Houtman、Eric A. Ortlund、Nathan T. Jui

  DOI：10.1016/j.bmcl.2020.127293

  日期：2020.8

  approach to overcome this limitation, identified that bridgehead substitution is necessary for LRH-1 activation, and described an alternative class of bridgehead substituents for effective LRH-1 agonist development. We determined the crystal structure of LRH-1 bound to a bridgehead-modified compound, revealing a promising opportunity to target novel regions of the ligand binding pocket to alter LRH-1

  LRH-1 是一种调节脂质代谢和稳态的核受体，使其成为治疗糖尿病和非酒精性脂肪肝的有吸引力的靶点。基于我们实验室最新的配体结合结构信息，我们设计了一系列新的 LRH-1 激动剂，通过增加极性相互作用进一步与 LRH-1 结合。虽然目前该支架的合成方法在很大程度上允许对激动剂核心进行装饰，但桥头取代基的显着变化在机械上被排除。我们开发了一种新的合成方法来克服这一限制，确定桥头取代对于 LRH-1 激活是必要的，并描述了用于有效开发 LRH-1 激动剂的另一类桥头取代基。我们确定了与桥头修饰化合物结合的 LRH-1 的晶体结构，揭示了靶向配体结合袋的新区域以改变 LRH-1 靶基因表达的有希望的机会。
• Small Molecule Agonists of the Orphan Nuclear Receptors Steroidogenic Factor-1 (SF-1, NR5A1) and Liver Receptor Homologue-1 (LRH-1, NR5A2)
  作者：Richard J. Whitby、Jozef Stec、Raymond D. Blind、Sally Dixon、Lisa M. Leesnitzer、Lisa A. Orband-Miller、Shawn P. Williams、Timothy M. Willson、Robert Xu、William J. Zuercher、Fang Cai、Holly A. Ingraham

  DOI：10.1021/jm1014296

  日期：2011.4.14

  The crystal structure of LRH-1 ligand binding domain bound to our previously reported agonist 3-(E-oct-4-en-4-y1)-1-phenylamino-2-phenyl-cis-bicyclo[3.3.0]oct-2-ene 5 is described. Two new classes of agonists in which the bridgehead anilino group from our first series was replaced with an alkoxy or 1-ethenyl group were designed, synthesized, and tested for activity in a peptide recruitment assay. Both new classes gave very active compounds, particularly against SF-1. Structure-activity studies led to excellent dual-LRH-1/SF-1 agonists (e.g., RJW100) as well as compounds selective for LRH-1 (RJW101) and SF-1 (RJW102 and RJW103). The series based on 1-ethenyl substitution was acid stable, overcoming a significant drawback of our original bridgehead anilino-substituted series. Initial studies on the regulation of gene expression in human cell lines showed excellent, reproducible activity at endogenous target genes.