Boc-(pMe)Phe-N(CH3)-OCH3 | 289681-18-1

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: Boc-(pMe)Phe-N(CH3)-OCH3
• 英文别名: tert-butyl N-[(2S)-1-[methoxy(methyl)amino]-3-(4-methylphenyl)-1-oxopropan-2-yl]carbamate
• CAS: 289681-18-1
• 化学式: C₁₇H₂₆N₂O₄
• 分子量: 322.404
• InChiKey: ZALNELQQTRISMJ-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  23
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  67.9
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Boc-(pMe)Phe-N(CH3)-OCH3 在 lithium aluminium tetrahydride 作用下， 以 乙醚 为溶剂， 生成 ((S)-1-Formyl-2-p-tolyl-ethyl)-carbamic acid tert-butyl ester
  参考文献：
  名称：

  Novel cell-penetrating α-keto-amide calpain inhibitors as potential treatment for muscular dystrophy

  摘要：

  Dipeptide-derived alpha-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC50 values down to 25 nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.08.064
• 作为产物：
  描述：

  BOC-L-4-甲基苯丙氨酸 、 N-甲基-N-甲氧基胺盐酸盐 在 N-甲基吗啉 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以90%的产率得到Boc-(pMe)Phe-N(CH3)-OCH3
  参考文献：
  名称：

  Novel cell-penetrating α-keto-amide calpain inhibitors as potential treatment for muscular dystrophy

  摘要：

  Dipeptide-derived alpha-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC50 values down to 25 nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease. (c) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2005.08.064

文献信息

• Further Studies on Nociceptin-Related Peptides:  Discovery of a New Chemical Template with Antagonist Activity on the Nociceptin Receptor
  作者：Remo Guerrini、Girolamo Calo'、Raffaella Bigoni、Anna Rizzi、Katia Varani、Geza Toth、Stefania Gessi、Eiji Hashiba、Yoshio Hashimoto、David G. Lambert、Pier Andrea Borea、Roberto Tomatis、Severo Salvadori、Domenico Regoli

  DOI：10.1021/jm990075h

  日期：2000.7.1

  Three series of nociceptin (NC)-related peptides were synthesized and their abilities (i) to bind to the NC sites expressed in mouse forebrain membranes, (ii) to inhibit the electrically evoked contraction of the mouse vas deferens, and (iii) to inhibit forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human recombinant NC receptor (CHONCR) were investigated. The compounds of the first series (a series) have an ordinary Xaa(1)-Gly(2) bond, those of the second series (b series) have a Xaa(1)Psi(CH2-NH)Gly(2) pseudopeptide bond, and those of the third series (c series) have a peptoid (Nxaa(1)-Gly(2)) structure. The affinity values measured in the binding assay and in the two functional assays with the compounds of the three series showed high levels of correlation. Thus, (I) the compounds of the a series in which Phe(1) was substituted with Tyr, Cha, or Leu acted as potent NC receptor agonists; (II) the b series compounds behaved as NC receptor antagonists in the mouse vas deferens and as full agonists in CHONCR cells with different potencies depending on the first amino acid residue, [Phe(1)Psi(CH2-NH)Gly(2)]NC(1-17)NH2 and [Phe(1)Psi(CH2-NH)Gly(2)]NC(1-13)NH2 being the most potent compounds; (III) the compounds of the third series were all inactive both as agonists and as antagonists with the exception of [Nphe(1)]NC(1-17)NH2 and [Nphe(1)]NC(1-13)NH2, which behaved as NC receptor antagonists both in the isolated tissue and in CHONCR cells (pK(B) 6.1-6.4). In conclusion, this study demonstrates that chemical requirements for NC receptor agonists are different from those of antagonists. Moreover, modifications of the steric orientation of the aromatic residue Phe(1) in the NC sequence as obtained with the pseudopeptide bond between Phe(1) and Gly(2) or with the displacement of the benzyl side chain by one atom, as in Nphe(1), lead respectively to reduction or elimination of efficacy. Indeed, in contrast to [Phe(1)Psi(CH2-NH)Gly(2)]NC(1-13)NH2 which has been reported to exhibit agonist activity in several assays involving either central or recombinant NC receptors, [Nphe(1)]NC(1-13)NH2 antagonizes the effect of NC at human recombinant NC receptors and in the mouse tail withdrawal assay.
• Defining the Determinants of Specificity of <i>Plasmodium</i> Proteasome Inhibitors
  作者：Euna Yoo、Barbara H. Stokes、Hanna de Jong、Manu Vanaerschot、TRS Kumar、Nina Lawrence、Mathew Njoroge、Arnold Garcia、Renier Van der Westhuyzen、Jeremiah D. Momper、Caroline L. Ng、David A. Fidock、Matthew Bogyo

  DOI：10.1021/jacs.8b06656

  日期：2018.9.12

  The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human beta\2 and beta 5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.