N¹-((2S,3S)-4-(4-carbamoyl-1H-pyrazol-1-yl)-3-hydroxy-1-phenylbutan-2-yl)-N³-((R)-1-(4-fluorophenyl)ethyl)-5-(N-methylmethylsulfonamido)isophthalamide | 1470073-18-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N¹-((2S,3S)-4-(4-carbamoyl-1H-pyrazol-1-yl)-3-hydroxy-1-phenylbutan-2-yl)-N³-((R)-1-(4-fluorophenyl)ethyl)-5-(N-methylmethylsulfonamido)isophthalamide
• 英文别名: 3-N-[(2S,3S)-4-(4-carbamoylpyrazol-1-yl)-3-hydroxy-1-phenylbutan-2-yl]-1-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzene-1,3-dicarboxamide
• CAS: 1470073-18-7
• 化学式: C₃₂H₃₅FN₆O₆S
• 分子量: 650.731
• InChiKey: QLUUUWVBQOCZQZ-YMUMJAELSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  46
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  185
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1-[(2S,3S)-3-[[3-[[(1R)-1-(4-fluorophenyl)ethyl]carbamoyl]-5-[methyl(methylsulfonyl)amino]benzoyl]amino]-2-hydroxy-4-phenylbutyl]pyrazole-4-carboxylic acid 在 氯化铵 、 1-羟基苯并三唑 、 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 N,N-二甲基甲酰胺 为溶剂， 反应 0.42h， 以68.3%的产率得到N¹-((2S,3S)-4-(4-carbamoyl-1H-pyrazol-1-yl)-3-hydroxy-1-phenylbutan-2-yl)-N³-((R)-1-(4-fluorophenyl)ethyl)-5-(N-methylmethylsulfonamido)isophthalamide
  参考文献：
  名称：

  羟乙基吡唑类化合物或氨乙基吡唑类化合物 及其制备方法和用途

  摘要：

  本发明公开了如下述通式I表示的羟乙基吡唑类化合物或氨乙基吡唑类化合物及其制备方法和用途。通过生物活性测试证明，该类化合物具有明显的抑制β‑分泌酶的活性。因此，本发明的羟乙基吡唑类化合物或氨乙基吡唑类化合物可作为β‑分泌酶的抑制剂而用于预防或对症治疗老年性痴呆。

  公开号：

  CN103508957B

文献信息

• 羟乙基吡唑类化合物或氨乙基吡唑类化合物 及其制备方法和用途
  申请人：中国科学院上海药物研究所

  公开号：CN103508957B

  公开（公告）日：2017-02-08

  本发明公开了如下述通式I表示的羟乙基吡唑类化合物或氨乙基吡唑类化合物及其制备方法和用途。通过生物活性测试证明，该类化合物具有明显的抑制β‑分泌酶的活性。因此，本发明的羟乙基吡唑类化合物或氨乙基吡唑类化合物可作为β‑分泌酶的抑制剂而用于预防或对症治疗老年性痴呆。
• Discovery of pyrazole as C-terminus of selective BACE1 inhibitors
  作者：Yiquan Zou、Lei Xu、Wuyan Chen、Yiping Zhu、Tiantian Chen、Yan Fu、Li Li、Lanping Ma、Bing Xiong、Xin Wang、Jian Li、Jianhua He、Haiyan Zhang、Yechun Xu、Jia Li、Jingkang Shen

  DOI：10.1016/j.ejmech.2013.06.027

  日期：2013.10

  We recently discovered and reported dual inhibitor 5 of AChE and BACE1 with N-benzylpiperidine ethyl as C-terminus. Compound 5 showed potent inhibitory activities for BACE1, and could reduce endogenous A beta(1-40) production in APP transgenic mice. In present work, we rapidly identified substituted triazole as the C-terminus of compound 5 by replacing the benzylpiperidine ethyl group with click chemistry and tested these synthesized compounds by in situ screening assay. As revealed by the crystal structures of BACE1 in complex with our triazole compound 12, we found that Pro70 and Thr72 located in the flap region were the critical components for binding with these inhibitors. With the aid of the crystal structure, a new series of five-membered heterocyclic compounds was prepared in order to explore the structure activity relationship (SAR) of this class of molecules. From these efforts, pyrazole was discovered as a novel C-terminus of BACE1 inhibitors. After further modification of pyrazole with variable substituents, compound 37 exhibited good potency in enzyme inhibition assay (IC50 = 0.025 mu M) and compound 33 showed moderate inhibition effects on A beta production of APP transfected HEK293 cells. Moreover, these pyrazole derivatives demonstrated good selectivity versus cathepsin D. Our results indicated that the vicinity of Pro70 and Thr72 might be utilized as a subsite, and the discovered pyrazole derivatives might provide useful hints for developing novel BACE1 inhibitors as anti-AD drugs. (C) 2013 Elsevier Masson SAS. All rights reserved.