N-(((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-10-(3-(naphthalen-1-yl)ureido)-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocin-2-yl)methyl)-N-methyl-2,3-dihydrobenzo-[b][1,4]dioxine-6-sulfonamide | 1314958-91-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-(((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-10-(3-(naphthalen-1-yl)ureido)-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocin-2-yl)methyl)-N-methyl-2,3-dihydrobenzo-[b][1,4]dioxine-6-sulfonamide
• 英文别名: BRD0476, probe ML187；1-[(2R,3R)-2-[[2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl(methyl)amino]methyl]-5-[(2S)-1-hydroxypropan-2-yl]-3-methyl-6-oxo-3,4-dihydro-2H-1,5-benzoxazocin-10-yl]-3-(1-naphthalenyl)urea；1-[(2R,3R)-2-[[2,3-dihydro-1,4-benzodioxin-6-ylsulfonyl(methyl)amino]methyl]-5-[(2S)-1-hydroxypropan-2-yl]-3-methyl-6-oxo-3,4-dihydro-2H-1,5-benzoxazocin-10-yl]-3-naphthalen-1-ylurea
• CAS: 1314958-91-2
• 化学式: C₃₅H₃₈N₄O₈S
• 分子量: 674.775
• InChiKey: YDFFDCBBGWXONN-MODXFSQWSA-N

物化性质

• 密度：
  1.364±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  48
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  155
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  2,3-二氢-1,4-苯并二氧-6-磺酰氯 在 2,6-二甲基吡啶 、 palladium 10% on activated carbon 、 氢气 、 1,8-双二甲氨基萘 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 乙醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 23.75h， 生成 N-(((2R,3R)-5-((S)-1-hydroxypropan-2-yl)-3-methyl-10-(3-(naphthalen-1-yl)ureido)-6-oxo-3,4,5,6-tetrahydro-2H-benzo[b][1,5]oxazocin-2-yl)methyl)-N-methyl-2,3-dihydrobenzo-[b][1,4]dioxine-6-sulfonamide
  参考文献：
  名称：

  Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction in β-Cells with Improved Aqueous Solubility

  摘要：

  We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced beta-cell apoptosis. Herein, we report the synthesis and biological evaluation of I and analogues with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogues with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that 1 and analogues inhibit STAT1 signal transduction induced by IFN-gamma.

  DOI：

  10.1021/jm400397x

文献信息

• Synthesis of a Novel Suppressor of β-Cell Apoptosis via Diversity-Oriented Synthesis
  作者：Danny Hung-Chieh Chou、Jeremy R. Duvall、Baudouin Gerard、Haibo Liu、Bhaumik A. Pandya、Byung-Chul Suh、Erin M. Forbeck、Patrick Faloon、Bridget K. Wagner、Lisa A. Marcaurelle

  DOI：10.1021/ml200120m

  日期：2011.9.8

  The synthesis of a stereochemically diverse library of medium-sized rings accessible via a "build/couple/pair" strategy is described. Key aspects of the synthesis include SNAr cycloetherification of a linear amine template to afford eight stereoisomeric eight-membered lactams and subsequent solid-phase diversification of these scaffolds to yield a 6488-membered library. Screening of this compound collection in a cell-based assay for the suppression of cytokine-induced beta-cell apoptosis resulted in the identification of a small-molecule suppressor capable of restoring glucose-stimulated insulin secretion in a rat beta-cell line. The presence of all stereoisomers in the screening collection enabled preliminary determination of the structural and stereochemical requirements for cellular activity, while efficient follow-up chemistry afforded BRD0476 (probe ML187), which had an approximately 3-fold increase in activity. These results demonstrate the utility of diversity-oriented synthesis to probe discovery using cell-based screening and the importance of including stereochemical diversity in screening collections for the development of stereo/structure-activity relationships.
• [EN] COMPOUNDS AND METHODS FOR TREATING AUTOIMMUNE DISEASES<br/>[FR] COMPOSÉS ET PROCÉDÉS POUR TRAITER DES MALADIES AUTO-IMMUNES
  申请人：BROAD INST INC

  公开号：WO2012061754A3

  公开（公告）日：2012-08-02
• TARGETED DELIVERY TO BETA CELLS
  申请人：THE BROAD INSTITUTE , INC.

  公开号：US20200384115A1

  公开（公告）日：2020-12-10

  The disclosure includes zinc prodrugs for targeted delivery of therapeutic, diagnostic or imaging agents to β-cells and methods of use therefor. The disclosure also includes targeted delivery of small molecules to β-cells that stabilize and activate CRISPR effector proteins comprising at least one destabilization domain, to enable CRISPR-based genome editing and transcriptional activation or repression in β-cells.
• US8741905B2
  申请人：——

  公开号：US8741905B2

  公开（公告）日：2014-06-03
• Small-Molecule Inhibitors of Cytokine-Mediated STAT1 Signal Transduction in β-Cells with Improved Aqueous Solubility
  作者：Stephen S. Scully、Alicia J. Tang、Morten Lundh、Carrie M. Mosher、Kedar M. Perkins、Bridget K. Wagner

  DOI：10.1021/jm400397x

  日期：2013.5.23

  We previously reported the discovery of BRD0476 (1), a small molecule generated by diversity-oriented synthesis that suppresses cytokine-induced beta-cell apoptosis. Herein, we report the synthesis and biological evaluation of I and analogues with improved aqueous solubility. By replacing naphthyl with quinoline moieties, we prepared active analogues with up to a 1400-fold increase in solubility from 1. In addition, we demonstrated that 1 and analogues inhibit STAT1 signal transduction induced by IFN-gamma.