N-[4-(4-acetyl-piperazin-1-yl)-2-fluoro-benzyl]-N-cyclobutyl-1-(4-fluorophenyl)-methanesulfonamide | 1445901-75-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: N-[4-(4-acetyl-piperazin-1-yl)-2-fluoro-benzyl]-N-cyclobutyl-1-(4-fluorophenyl)-methanesulfonamide
• 英文别名: N-[[4-(4-acetylpiperazin-1-yl)-2-fluorophenyl]methyl]-N-cyclobutyl-1-(4-fluorophenyl)methanesulfonamide
• CAS: 1445901-75-6
• 化学式: C₂₄H₂₉F₂N₃O₃S
• 分子量: 477.575
• InChiKey: NCJSAYJJAWXCGU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.46
• 拓扑面积：
  69.3
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  4-溴-1-(二甲氧基甲基)-2-氟苯 在 palladium diacetate 、 三乙酰氧基硼氢化钠 、 溶剂黄146 、 N,N-二异丙基乙胺 、 sodium t-butanolate 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 1,2-二氯乙烷 为溶剂， 生成 N-[4-(4-acetyl-piperazin-1-yl)-2-fluoro-benzyl]-N-cyclobutyl-1-(4-fluorophenyl)-methanesulfonamide
  参考文献：
  名称：

  Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action

  摘要：

  A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenyl-sulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.

  DOI：

  10.1021/ml500420y

文献信息

• BENZYL SULFONAMIDE DERIVATIVES AS RORC MODULATORS
  申请人：Genentech, Inc.

  公开号：US20130190288A1

  公开（公告）日：2013-07-25

  Compounds of the formula I: or pharmaceutically acceptable salts thereof, wherein m, n, A, X 1 , X 2 , X 3 , X 4 , R 1 , R 2 , R 3a , R 3b , R 4a and R 4b are as defined herein. Also disclosed are methods of making the compounds and using the compounds for treatment of inflammatory diseases such as arthritis.

  化合物I的公式或其药学上可接受的盐，其中m、n、A、X1、X2、X3、X4、R1、R2、R3a、R3b、R4a和R4b的定义如本文所述。还公开了制备该化合物的方法，并将该化合物用于治疗炎症性疾病，如关节炎。
• US9216988B2
  申请人：——

  公开号：US9216988B2

  公开（公告）日：2015-12-22
• Minor Structural Change to Tertiary Sulfonamide RORc Ligands Led to Opposite Mechanisms of Action
  作者：Olivier René、Benjamin P. Fauber、Gladys de Leon Boenig、Brenda Burton、Céline Eidenschenk、Christine Everett、Alberto Gobbi、Sarah G. Hymowitz、Adam R. Johnson、James R. Kiefer、Marya Liimatta、Peter Lockey、Maxine Norman、Wenjun Ouyang、Heidi A. Wallweber、Harvey Wong

  DOI：10.1021/ml500420y

  日期：2015.3.12

  A minor structural change to tertiary sulfonamide RORc ligands led to distinct mechanisms of action. Co-crystal structures of two compounds revealed mechanistically consistent protein conformational changes. Optimized phenyl-sulfonamides were identified as RORc agonists while benzylsulfonamides exhibited potent inverse agonist activity. Compounds behaving as agonists in our biochemical assay also gave rise to an increased production of IL-17 in human PBMCs whereas inverse agonists led to significant suppression of IL-17 under the same assay conditions. The most potent inverse agonist compound showed >180-fold selectivity over the ROR isoforms as well as all other nuclear receptors that were profiled.