2-(2-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-N-hydroxyacetamide | 296765-94-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 2-(2-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-N-hydroxyacetamide
• 英文别名: QHL1；[2-(3,4-dihydro-1H-isoquinoline-2-sulfonyl)phenyl]-N-hydroxyacetamide；2-[2-(3,4-dihydro-1H-isoquinolin-2-ylsulfonyl)phenyl]-N-hydroxyacetamide
• CAS: 296765-94-1
• 化学式: C₁₇H₁₈N₂O₄S
• 分子量: 346.407
• InChiKey: IOHLYYFAABEJOI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  95.1
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  butyl 2-(2-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)acetate 在 羟胺 、 potassium hydroxide 作用下， 以 四氢呋喃 、 水 为溶剂， 以47 %的产率得到2-(2-((3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)phenyl)-N-hydroxyacetamide
  参考文献：
  名称：

  The Discovery of New Inhibitors of Insulin-Regulated Aminopeptidase by a High-Throughput Screening of 400,000 Drug-like Compounds

  摘要：

  With the ambition to identify novel chemical starting points that can be further optimized into small drug-like inhibitors of insulin-regulated aminopeptidase (IRAP) and serve as potential future cognitive enhancers in the clinic, we conducted an ultra-high-throughput screening campaign of a chemically diverse compound library of approximately 400,000 drug-like small molecules. Three biochemical and one biophysical assays were developed to enable large-scale screening and hit triaging. The screening funnel, designed to be compatible with high-density microplates, was established with two enzyme inhibition assays employing either fluorescent or absorbance readouts. As IRAP is a zinc-dependent enzyme, the remaining active compounds were further evaluated in the primary assay, albeit with the addition of zinc ions. Rescreening with zinc confirmed the inhibitory activity for most compounds, emphasizing a zinc-independent mechanism of action. Additionally, target engagement was confirmed using a complementary biophysical thermal shift assay where compounds causing positive/negative thermal shifts were considered genuine binders. Triaging based on biochemical activity, target engagement, and drug-likeness resulted in the selection of 50 qualified hits, of which the IC50 of 32 compounds was below 3.5 µM. Despite hydroxamic acid dominance, diverse chemotypes with biochemical activity and target engagement were discovered, including non-hydroxamic acid compounds. The most potent compound (QHL1) was resynthesized with a confirmed inhibitory IC50 of 320 nM. Amongst these compounds, 20 new compound structure classes were identified, providing many new starting points for the development of unique IRAP inhibitors. Detailed characterization and optimization of lead compounds, considering both hydroxamic acids and other diverse structures, are in progress for further exploration.

  DOI：

  10.3390/ijms25074084

文献信息

• Hydroxamic and carboxylic acid derivatives
  申请人：——

  公开号：US20030022893A1

  公开（公告）日：2003-01-30

  The subject invention concerns methods and compounds that have utility in the treatment of a condition associated with matrix metalloproteinase, ADAM or ADAM-TS enzymes, a condition that is mediated by TNF &agr; or a condition involving a membrane-shedding event that is mediated by a metalloproteinase. Compounds of the invention are of formula I (B) 2 N—X—(CH 2 ) m -W-(CR 1 R 2 ) n —COY  (I) wherein n=0 or 1; m=0 or 1; X is S(O) 1-2 ; Y is OH or NHOH; W is aryl or heteroaryl; and the other groups are as defined herein.

  本发明涉及用于治疗与基质金属蛋白酶、ADAM或ADAM-TS酶相关的疾病、由TNFα介导的疾病或由金属蛋白酶介导的膜剥离事件相关的疾病的方法和化合物。本发明的化合物的化学式为I（B）2N—X—（CH2）m-W-（CR1R2）n—COY（I），其中n=0或1；m=0或1；X为S（O）1-2；Y为OH或NHOH；W为芳基或杂环芳基；其他基团如本文所定义。
• ヒドロキサムおよびカルボン酸誘導体
  申请人：ダーウィン・ディスカバリー・リミテッド

  公开号：JP2003525203A

  公开（公告）日：2003-08-26

  \n (57)【要約】\nマトリックスメタロプロテイナーゼ、ＡＤＡＭまたはＡＤＡＭ-ＴＳ酵素と関連する疾患、ＴＮＦαが媒介する疾患または、メタロプロテイナーゼが媒介する膜脱落現象が関与する疾患の治療に有用な化合物(その多くは新規である)は、式(Ｉ):(Ｂ)２Ｎ-Ｘ-(ＣＨ２)ｍ-Ｗ-(ＣＲ１Ｒ２)ｎ-ＣＯＹ(式中、ｎ＝０または１；ｍ＝０または１；ＸはＳ(Ｏ)１-２；ＹはＯＨまたはＮＨＯＨ；Ｗはアリールまたはヘテロアリール；および、他の基は本明細書中に定義するものである)の化合物である。\n

  \(57) [摘要] 有助于治疗与Јn基质金属蛋白酶、ADAM或ADAM-TS酶有关的疾病、由TNFα介导的疾病或涉及金属蛋白酶介导的膜脱落现象的疾病的化合物（其中许多是新型化合物）是那些具有式(I)的化合物：(B)2N-X-(CH2)m-W-(CR1R2)n-COY（其中 n = 0 或 1；m = 0 或 1；X 为 S(O)1-2；Y 为 OH 或 NHOH；W 为芳基或杂芳基；其他基团如本文所定义）。\n
• HYDROXAMIC AND CARBOXYLIC ACID DERIVATIVES
  申请人：Darwin Discovery Limited

  公开号：EP1163213A1

  公开（公告）日：2001-12-19
• US6465468B1
  申请人：——

  公开号：US6465468B1

  公开（公告）日：2002-10-15
• [EN] HYDROXAMIC AND CARBOXYLIC ACID DERIVATIVES<br/>[FR] DERIVES D'ACIDE HYDROXAMIXE ET CARBOXYLIQUE
  申请人：DARWIN DISCOVERY LTD

  公开号：WO2000056704A1

  公开（公告）日：2000-09-28

  Compounds (many of which are new) that have utility in the treatment of a condition associated with matrix metalloproteinase, ADAM or ADAM-TS enzymes, a condition that is mediated by TNF α or a condition involving a membrane-shedding event that is mediated by a metalloproteinase, are of formula (I): (B)2N-X-(CH2)m-W-(CR1R2)n-COY, wherein n= 0 or 1; m =0 or 1; X is S(O)1-2; Y is OH or NHOH; W is aryl or heteroaryl; and the other groups are as defined herein.