(3R-trans)-1-[(1-Methyl-4-imidazole)sulfonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (3R-trans)-1-[(1-Methyl-4-imidazole)sulfonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide
• 英文别名: (3R,4S)-3-N-hydroxy-1-(1-methylimidazol-4-yl)sulfonyl-4-N-[4-[(2-methylquinolin-4-yl)methoxy]phenyl]piperidine-3,4-dicarboxamide
• 化学式: C₂₈H₃₀N₆O₆S
• 分子量: 578.649
• InChiKey: BPBXDIWULCWTST-ZEQRLZLVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  41
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  164
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (3R,4S)-4-[4-(2-Methyl-quinolin-4-ylmethoxy)-phenylcarbamoyl]-piperidine-3-carboxylic acid 在 N-甲基吗啉 、 盐酸羟胺 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 水 、 N,N-二甲基甲酰胺 为溶剂， 生成 (3R-trans)-1-[(1-Methyl-4-imidazole)sulfonyl]-N3-hydroxy-N4-[4-[(2-methyl-4-quinolinyl)methoxy]phenyl]-3,4-piperidinedicarboxamide
  参考文献：
  名称：

  Rational design, synthesis and structure–activity relationships of a cyclic succinate series of TNF-α converting enzyme inhibitors. Part 2: lead optimization

  摘要：

  Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-{[4-(4-quinolinyloxymethyl)anilinyl]carbonyl}-1-cyclo-hexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-{[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide] exhibited an IC50 value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.09.057

文献信息

• Novel Cyclic hydroxamic acid as metalloproteinase inhibitors
  申请人：——

  公开号：US20030139597A1

  公开（公告）日：2003-07-24

  The present application describes novel cyclic hydroxamic acids of formula I: 1 or pharmaceutically acceptable salt forms thereof, wherein ring B is a 5-7 membered cyclic system containing from 0-2 heteroatoms selected from O, N, NR a , and S(O) p , and 0-1 carbonyl groups and the other variables are defined in the present specification, which are useful as metalloprotease inhibitors.

  本申请描述了新型的环状羟肟酸，其化学式为I:1或其药用盐形式，其中环B为包含0-2个来自O、N、NRa和S(O)p的杂原子和0-1个羰基基团的5-7元环系统，而其他变量在本说明书中有定义，这些化合物可用作金属蛋白酶抑制剂。
• US6429213B1
  申请人：——

  公开号：US6429213B1

  公开（公告）日：2002-08-06
• US6858626B2
  申请人：——

  公开号：US6858626B2

  公开（公告）日：2005-02-22
• Rational design, synthesis and structure–activity relationships of a cyclic succinate series of TNF-α converting enzyme inhibitors. Part 2: lead optimization
  作者：Chu-Biao Xue、Xiaohua He、John Roderick、Ronald L Corbett、James J.-W Duan、Rui-Qin Liu、Maryanne B Covington、Mingxin Qian、Maria D Ribadeneira、Krishna Vaddi、David D Christ、Robert C Newton、James M Trzaskos、Ronald L Magolda、Ruth R Wexler、Carl P Decicco

  DOI：10.1016/j.bmcl.2003.09.057

  日期：2003.12

  Modifications of the lead TACE inhibitor 1 (N-hydroxy-trans-2-[4-(4-quinolinyloxymethyl)anilinyl]carbonyl}-1-cyclo-hexanecarboxamide) at the cyclohexyl ring and the quinoline moiety led to the identification of a series of piperidine containing TACE inhibitors with potent activity in the inhibition of TNF-alpha release in the whole blood assay (WBA). The most potent analogue IM491 [N-hydroxy-(5S,6S)-1-methyl-6-[4-(2-methyl-4-quinolinylmethoxy)anilinyl]carbonyl}-5-piperidinecarboxamide] exhibited an IC50 value of 20 nM in WBA with excellent selectivity over MMP-1, -2 and -9 and is orally bioavailable with an F value of 43% in beagle dogs. (C) 2003 Elsevier Ltd. All rights reserved.