N-[[(2R)-1-[4-(butylamino)-6-[(3-methylphenyl)methylamino]-1,3,5-triazin-2-yl]pyrrolidin-2-yl]methyl]-4-propylbenzenesulfonamide | 1394122-48-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 三嗪类
• 英文名称: N-[[(2R)-1-[4-(butylamino)-6-[(3-methylphenyl)methylamino]-1,3,5-triazin-2-yl]pyrrolidin-2-yl]methyl]-4-propylbenzenesulfonamide
• CAS: 1394122-48-5
• 化学式: C₂₉H₄₁N₇O₂S
• 分子量: 551.756
• InChiKey: YTWFUMIEHKSPPN-RUZDIDTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.7
• 重原子数：
  39
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  121
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  3-甲基苄胺 在 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 反应 0.75h， 生成 N-[[(2R)-1-[4-(butylamino)-6-[(3-methylphenyl)methylamino]-1,3,5-triazin-2-yl]pyrrolidin-2-yl]methyl]-4-propylbenzenesulfonamide
  参考文献：
  名称：

  Discovery of Highly Potent and Selective Small Molecule ADAMTS-5 Inhibitors That Inhibit Human Cartilage Degradation via Encoded Library Technology (ELT)

  摘要：

  The metalloprotease ADAMTS-5 is considered a potential target for the treatment of osteoarthritis. To identify selective inhibitors of ADAMTS-5, we employed encoded library technology (ELT), which enables affinity selection of small molecule binders from complex mixtures by DNA tagging. Selection of ADAMTS-5 against a four-billion member ELT library led to a novel inhibitor scaffold not containing a classical zinc-binding functionality. One exemplar, (R)-N-((1-(4-(but-3-en-1-ylamino)-6-(((2-(thiophen-2-yl)thiazol-4-yl)methyl)amino)-1,3,5-triazin-2-yl)pyrrolidin-2-yl)methyl)-4-propylbenzenesulfonamide (8), inhibited ADAMTS-5 with IC50 = 30 nM, showing >50-fold selectivity against ADAMTS-4 and >1000-fold selectivity against ADAMTS-1, ADAMTS-13, MMP-13, and TACE. Extensive SAR studies showed that potency and physicochemical properties of the scaffold could be further improved. Furthermore, in a human osteoarthritis cartilage explant study, compounds 8 and 15f inhibited aggrecanase-mediated (374)ARGS neoepitope release from aggrecan and glycosaminoglycan in response to IL-1 beta/OSM stimulation. This study provides the first small molecule evidence for the critical role of ADAMTS-5 in human cartilage degradation.

  DOI：

  10.1021/jm300449x

文献信息

• MODULATING ADIPOSE TISSUE AND ADIPOGENESIS
  申请人：Katholieke Universiteit Leuven KU Leuven Research & Development

  公开号：EP3209794A1

  公开（公告）日：2017-08-30