5,10-Dimethoxy-2,2,4-trimethyl-2,5-dihydro-1H-6-oxa-1-aza-chrysene | 239071-00-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: 5,10-Dimethoxy-2,2,4-trimethyl-2,5-dihydro-1H-6-oxa-1-aza-chrysene
• 英文别名: 5,10-Dimethoxy-2,2,4-trimethyl-1,5-dihydrochromeno[3,4-f]quinoline
• CAS: 239071-00-2
• 化学式: C₂₁H₂₃NO₃
• 分子量: 337.419
• InChiKey: CCNZMKGIMPKEFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  25
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  39.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5,10-Dimethoxy-2,2,4-trimethyl-2,5-dihydro-1H-6-oxa-1-aza-chrysene 在 lithium hydroxide 、 三氟化硼乙醚 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 为溶剂， 生成 (10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-6-oxa-1-aza-chrysen-5-yl)-acetic acid
  参考文献：
  名称：

  Nonsteroidal Selective Glucocorticoid Modulators:  the Effect of C-5 Alkyl Substitution on the Transcriptional Activation/Repression Profile of 2,5-Dihydro-10-methoxy-2,2,4-trimethyl-1H-[1]benzopyrano[3,4-f]quinolines

  摘要：

  The preparation and characterization of a series of selective glucocorticoid receptor modulators are described. The preliminary structure-activity relationship of nonaromatic C-5 substitution on the tetracyclic quinoline core showed a preference for small lipophilic side chains. Proper substitution at this position maintained the transcriptional repression of proinflammatory transcription factors while diminishing the transcriptional activation activity of the ligand/glucocorticoid receptor complex. The optimal compounds described in this study were the allyl analogue 18 and cyclopentyl analogue 32. These candidates showed slightly less potent, highly efficacious E-selectin repression with significantly reduced levels of glucocorticoid response element activation in reporter gene assays vs prednisolone. Allyl analogue 18 was evaluated in vivo. An oral dose of 18 showed an ED50 = 1.7 mg/kg as compared to 1.2 mg/kg for prednisolone in the Sephadex-induced pulmonary eosinophilia model and an ED50 = 15 mg/kg vs 4 mg/kg for prednisolone in the carrageenan-induced paw edema model.

  DOI：

  10.1021/jm010367u
• 作为产物：
  描述：

  1-methoxy-8-nitro-6H-dibenzo[b,d]pyran-6-one 在 palladium on activated charcoal 氢气 、 碘 、 二异丁基氢化铝 、 对甲苯磺酸 作用下， 以 1,4-二氧六环 、 正己烷 、 二氯甲烷 为溶剂， 反应 110.0h， 生成 5,10-Dimethoxy-2,2,4-trimethyl-2,5-dihydro-1H-6-oxa-1-aza-chrysene
  参考文献：
  名称：

  Synthesis and Characterization of Non-Steroidal Ligands for the Glucocorticoid Receptor:  Selective Quinoline Derivatives with Prednisolone-Equivalent Functional Activity

  摘要：

  A novel class of functional ligands for the human glucocorticoid receptor is described. Substituents in the C-10 position of the tetracyclic core are essential for glucocorticoid receptor (GR) selectivity versus other steroid receptors. The C-5 position is derivatized with meta-substituted aromatic groups, resulting in analogues with a high affinity for GR (K-i = 2.4-9.3 nM) and functional activity comparable to prednisolone in reporter gene assays of glucocorticoid-mediated gene transcription. The biological activity of these novel quinolines was also prednisolone-equivalent in whole cell assays of glucocorticoid function, and compound 13 was similar to prednisolone (po ED50 = 2.8 mpk for 13 vs ED50 = 1.2 mpk for prednisolone) in a rodent model of asthma (sephadex-induced eosinophil influx).

  DOI：

  10.1021/jm010228c

文献信息

• A Practical and Scaleable Synthesis of A-224817.0, a Novel Nonsteroidal Ligand for the Glucocorticoid Receptor
  作者：Yi-Yin Ku、Tim Grieme、Prasad Raje、Padam Sharma、Howard E. Morton、Mike Rozema、Steve A. King

  DOI：10.1021/jo0268613

  日期：2003.4.1

  A practical and scaleable synthesis of a novel nonsteroidal ligand for the glucocorticoid receptor A-224817.0 1A is described. The synthesis proceeds in seven steps starting from 1,3-dimethoxybenzene. The biaryl intermediate 5 was prepared by an optimized high-yielding and high-throughput Negishi protocol. The quinoline core 8 was constructed by using a modified Skraup reaction. The final product was obtained by a direct allylation reaction of lactol 10 with allyltrimethylsilane. The process was accomplished efficiently to produce 1A in 25% overall yield and >99% purity with simple and practical isolation and purification procedures.
• Differentiation of in vitro transcriptional repression and activation profiles of selective glucocorticoid modulators
  作者：Steven W Elmore、John K Pratt、Michael J Coghlan、Yue Mao、Brian E Green、David D Anderson、Michael A Stashko、Chun W Lin、Douglas Falls、Masaki Nakane、Loan Miller、Curtis M Tyree、Jeffrey N Miner、Ben Lane

  DOI：10.1016/j.bmcl.2004.01.044

  日期：2004.4

  The SAR at C-5 of the 10-methoxy-2,2,4-trimethylbenzopyrano[3,4-f]quinoline core leading to identification of (-) anti 1-methylcyclohexen-3-yl as the optimum substituent that imparts minimal GR mediated in vitro transcriptional activation while maintaining full transcriptional repression is described. The in vitro profile of these candidates in human cell assays relevant to the therapeutic window of glucocorticoid modulators is outlined. (C) 2004 Elsevier Ltd. All rights reserved.
• WO2021/118728
  申请人：——

  公开号：——

  公开（公告）日：——
• A Novel Radioligand Reveals Tissue Specific Pharmacological Modulation of Glucocorticoid Receptor Expression with Positron Emission Tomography
  作者：Yangjie Huang、Ning Zhao、Yung-hua Wang、Charles Truillet、Junnian Wei、Joseph E. Blecha、Henry F. VanBrocklin、Youngho Seo、Mohd Sayeed、Brian J. Feldman、Rahul Aggarwal、Spencer C. Behr、Hao Shao、David M. Wilson、Javier E. Villanueva-Meyer、Jason E. Gestwicki、Michael J. Evans

  DOI：10.1021/acschembio.9b01043

  日期：2020.6.19

  The complexity of glucocorticoid receptor (GR) signaling cannot be measured with direct tissue analysis in living subjects, which has stifled our understanding of GR's role in human physiology or disease and impeded the development of selective GR modulators. Herein, we report F-18-5-(4-fluorobenzyi)-10-methoxy-2,2,4-trimethyl-2,5-dihydro-1H-chromeno [3,4-f]-quinoline (F-18-YJHO8), a radioligand that enables noninvasive measurements of tissue autonomous GR expression levels in vivo with positron emission tomography (PET). YJHO8 potently binds GR (K-i similar to 0.4 nM) with similar to 100-fold selectivity compared to nuclear hormone receptors in the same subfamily. F-18-YJHO8 was prepared via Cu(OTf)(2)(py)(4)-mediated radiofluorination of an arylboronic acid pinacol ester with similar to 12% decay corrected radiochemical yield from the starting F-18-fluoride ion. We applied treatment with the tissue-wide GR agonist dexamethasone and adrenalectomy and generated an adipocyte specific GR knockout mouse to show that( 18)F-YJHO8 specifically binds GR in normal mouse tissues, including those for which aberrant GR expression is thought to drive severe diseases (e.g., brain, adipose tissue, kidneys). Remarkably, F-18-YJHO8 PET also revealed that JG231, a potent and bioavailable HSP70 inhibitor, selectively degrades GR only in the adipose tissue of mice, a finding that foreshadows how GR targeted PET might be integrated into drug discovery to screen for selective GR modulation at the tissue level, beyond the historical screening that was performed at the transcriptional level. In summary, F-18-YJHO8 enables a quantitative assessment of GR expression levels in real time among multiple tissues simultaneously, and this technology is a first step toward unraveling the daunting complexity of GR signaling and rationally engineering tissue specific therapeutic modulators in vivo.
• Synthesis and Characterization of Non-Steroidal Ligands for the Glucocorticoid Receptor:  Selective Quinoline Derivatives with Prednisolone-Equivalent Functional Activity
  作者：Michael J. Coghlan、Philip R. Kym、Steven W. Elmore、Alan X. Wang、Jay R. Luly、Denise Wilcox、Michael Stashko、Chun-Wei Lin、Jeffrey Miner、Curtis Tyree、Masaki Nakane、Peer Jacobson、Benjamin C. Lane

  DOI：10.1021/jm010228c

  日期：2001.8.1

  A novel class of functional ligands for the human glucocorticoid receptor is described. Substituents in the C-10 position of the tetracyclic core are essential for glucocorticoid receptor (GR) selectivity versus other steroid receptors. The C-5 position is derivatized with meta-substituted aromatic groups, resulting in analogues with a high affinity for GR (K-i = 2.4-9.3 nM) and functional activity comparable to prednisolone in reporter gene assays of glucocorticoid-mediated gene transcription. The biological activity of these novel quinolines was also prednisolone-equivalent in whole cell assays of glucocorticoid function, and compound 13 was similar to prednisolone (po ED50 = 2.8 mpk for 13 vs ED50 = 1.2 mpk for prednisolone) in a rodent model of asthma (sephadex-induced eosinophil influx).