N-(amino(3-chloro-5-vinylbenzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-4-carboxamide | 917386-26-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N-(amino(3-chloro-5-vinylbenzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-4-carboxamide
• 英文别名: N-[N'-[(3-chloro-5-ethenylphenyl)methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide
• CAS: 917386-26-6
• 化学式: C₂₂H₂₁ClN₄O₃
• 分子量: 424.887
• InChiKey: FZDNIXHRSZJWSD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.14
• 拓扑面积：
  103
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  乙烯基硼酸频哪醇酯 、 N-[N'-[(3-bromo-5-chlorophenyl)methyl]carbamimidoyl]-3-(4-methoxyphenyl)-5-methyl-1,2-oxazole-4-carboxamide 在 potassium phosphate 、 四(三苯基膦)钯 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 15.0h， 以33%的产率得到N-(amino(3-chloro-5-vinylbenzylamino)methylene)-3-(4-methoxyphenyl)-5-methylisoxazole-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

文献信息

• 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.