tert-butyl N-(4-amino-3-chloro-5-methylbenzyl)-N'-(3-(4-methoxyphenyl)-5-methylisothiazole-4-carbonyl)carbamimidoylcarbamate | 1402164-73-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: tert-butyl N-(4-amino-3-chloro-5-methylbenzyl)-N'-(3-(4-methoxyphenyl)-5-methylisothiazole-4-carbonyl)carbamimidoylcarbamate
• 英文别名: tert-butyl N-[N'-[(4-amino-3-chloro-5-methylphenyl)methyl]-N-[3-(4-methoxyphenyl)-5-methyl-1,2-thiazole-4-carbonyl]carbamimidoyl]carbamate
• CAS: 1402164-73-1；917475-50-4
• 化学式: C₂₆H₃₀ClN₅O₄S
• 分子量: 544.074
• InChiKey: OXNMGEQIFILUEG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  37
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.31
• 拓扑面积：
  156
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl N-(4-amino-3-chloro-5-methylbenzyl)-N'-(3-(4-methoxyphenyl)-5-methylisothiazole-4-carbonyl)carbamimidoylcarbamate 在 三乙胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 N-(amino(3-chloro-4-(2-(ethylamino)acetamido)-5-methylbenzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisothiazole-4-carboxamide
  参考文献：
  名称：

  Acyl Guanidine Inhibitors of β-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis

  摘要：

  This report describes the discovery and optimizition of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A beta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain A beta levels were not obtained.

  DOI：

  10.1021/jm300931y
• 作为产物：
  描述：

  2-甲基-2-丙基[(甲硫基)亚氨代甲酰基]氨基甲酸酯 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 tert-butyl N-(4-amino-3-chloro-5-methylbenzyl)-N'-(3-(4-methoxyphenyl)-5-methylisothiazole-4-carbonyl)carbamimidoylcarbamate
  参考文献：
  名称：

  Acyl Guanidine Inhibitors of β-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis

  摘要：

  This report describes the discovery and optimizition of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A beta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain A beta levels were not obtained.

  DOI：

  10.1021/jm300931y

文献信息

• Aminoacetamide acyl guanidines as beta-secretase inhibitors
  申请人：Gerritz Samuel

  公开号：US20060287287A1

  公开（公告）日：2006-12-21

  There is provided a series of substituted acyl guanidines of Formula (Ik) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R 2 , R 3 , R 4 , R 5 , R 25 , R 26 and R 27 as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by β-secretase and, more specifically, inhibit the production of Aβ-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to β-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.

  提供了一系列的取代酰基胍类化合物，符合以下化学式（Ik）或其立体异构体；或其药学上可接受的盐，其中R2、R3、R4、R5、R25、R26和R27如本文所定义，它们的药物组合物和使用方法。这些化合物抑制β-分泌酶对淀粉样前体蛋白（APP）的加工，更具体地说，抑制Aβ肽的产生。本公开涉及对β-淀粉样蛋白产生相关的神经疾病的治疗有用的化合物，如阿尔茨海默氏病和其他受抗淀粉样活性影响的病症。
• US7273882B2
  申请人：——

  公开号：US7273882B2

  公开（公告）日：2007-09-25
• [EN] AMINOACETAMIDE ACYL GUANIDINES AS BETA-SECRETASE INHIBITORS<br/>[FR] GUANIDINES D'ACYLE ACETAMIDE AMINE EN TANT QU'INHIBITEURS DE BETA-SECRETASE
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2007002220A2

  公开（公告）日：2007-01-04

  [EN] There is provided a series of substituted acyl guanidines of Formula (Ik) or a stereoisomer; or a pharmaceutically acceptable salt thereof, wherein R₂, R₃, R₄, R₅, R₂₅, R₂₆ and R₂₇ as defined herein, their pharmaceutical compositions and methods of use. These compounds inhibit the processing of amyloid precursor protein (APP) by ß-secretase and, more specifically, inhibit the production of Aß-peptide. The present disclosure is directed to compounds useful in the treatment of neurological disorders related to ß-amyloid production, such as Alzheimer's disease and other conditions affected by anti-amyloid activity.
  [FR] La présente invention a trait à une série de guanidines d'acyle substitués de formule (Ik), dans laquelle: R₂, R₃, R₄, R₅, R₂₅, R₂₆ et R₂₇ sont tels que définis dans la description, ou un stéréoisomère; ou un sel pharmaceutiquement acceptable de celles-ci; à leurs compositions pharmaceutiques et leurs procédés d'utilisation. Ces composés sont inhibiteurs du processus de la protéine précurseur d'amyloïde par la ß-sécrétase et, plus spécifiquement, inhibiteurs de la production de peptide Aß. La présente invention a également trait à des composés utiles dans le traitement de troubles neurologiques liés à la production de ß-amyloïde, tels que la maladie d'Alzheimer et d'autres conditions affectées par l'activité anti-amyloïde.
• Acyl Guanidine Inhibitors of β-Secretase (BACE-1): Optimization of a Micromolar Hit to a Nanomolar Lead via Iterative Solid- and Solution-Phase Library Synthesis
  作者：Samuel W. Gerritz、Weixu Zhai、Shuhao Shi、Shirong Zhu、Jeremy H. Toyn、Jere E. Meredith、Lawrence G. Iben、Catherine R. Burton、Charles F. Albright、Andrew C. Good、Andrew J. Tebben、Jodi K. Muckelbauer、Daniel M. Camac、William Metzler、Lynda S. Cook、Ramesh Padmanabha、Kimberley A. Lentz、Michael J. Sofia、Michael A. Poss、John E. Macor、Lorin A. Thompson

  DOI：10.1021/jm300931y

  日期：2012.11.8

  This report describes the discovery and optimizition of a BACE-1 inhibitor series containing an unusual acyl guanidine chemotype that was originally synthesized as part of a 6041-membered solid-phase library. The synthesis of multiple follow-up solid- and solution-phase libraries facilitated the optimization of the original micromolar hit into a single-digit nanomolar BACE-1 inhibitor in both radioligand binding and cell-based functional assay formats. The X-ray structure of representative inhibitors bound to BACE-1 revealed a number of key ligand:protein interactions, including a hydrogen bond between the side chain amide of flap residue Gln73 and the acyl guanidine carbonyl group, and a cation-pi interaction between Arg235 and the isothiazole 4-methoxyphenyl substituent. Following subcutaneous administration in rats, an acyl guanidine inhibitor with single-digit nanomolar activity in cells afforded good plasma exposures and a dose-dependent reduction in plasma A beta levels, but poor brain exposure was observed (likely due to Pgp-mediated efflux), and significant reductions in brain A beta levels were not obtained.