3-(R)-benzyloxycarbonyl-5-methylhexanoic acid | 129776-60-9

• 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: 3-(R)-benzyloxycarbonyl-5-methylhexanoic acid
• 英文别名: (3R)-3-(benzyloxycarbonyl)-5-methylhexanoic acid；benzyl (2R)-2-(Carboxymethyl)-4-methylpentanoate；benzyl (2R)-2-carboxymethyl-4-methylvalerate；(R)-2-isobutylmonobenzyl succinate；Benzyl(2R)-2-carboxymethyl-4-methylvalerate；(3R)-5-methyl-3-phenylmethoxycarbonylhexanoic acid
• CAS: 129776-60-9
• 化学式: C₁₅H₂₀O₄
• 分子量: 264.321
• InChiKey: CFMRKUYJARYXBX-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  19
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-(R)-benzyloxycarbonyl-5-methylhexanoic acid 在 4-二甲氨基吡啶 、 草酰氯 、 palladium on activated charcoal 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二甲基甲酰胺 作用下， 以 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 生成 pentafluorophenyl 2-(R)-isobutyl-3-(N-tert-butoxycarbonyl-N-(tert-butyl-dimethylsilyloxy)carbamoyl)propionate
  参考文献：
  名称：

  A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging

  摘要：

  Background: Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with F-18 and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo.Materials and methods: ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[F-18]fluorobenzoate ([F-18]SFB) for PET (positron emission tomography). The resulting radiotracer [F-18]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [F-18]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5 mg/kg ML5. Results: ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 +/- 2.0, 19.5 +/- 2.8, 2.0 +/- 0.2 and 5.7 +/- 2.2 nM and 12.5 +/- 3.1, 31.5 +/- 13.7, 138.0 +/- 10.9 and 24.7 +/- 2.8 nM. Radiochemical yield of HPLC-purified [F-18]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [F-18]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10 mu M of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [F-18]FB-ML5 showed a SUVmean of 0.145 +/- 0.064 (n = 6) which decreased to 0.041 +/- 0.027 (n = 6) after target blocking (p < 0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2 +/- 7.3% (n = 2) of total radioactivity in plasma, at 90 min post injection (p.i.).Conclusion: The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with F-18. [F-18]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [F-18]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [F-18]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.11.013
• 作为产物：
  描述：

  4-甲基戊酸 在 正丁基锂 、 氯化亚砜 、 三氟乙酸 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 3-(R)-benzyloxycarbonyl-5-methylhexanoic acid
  参考文献：
  名称：

  A dual inhibitor of matrix metalloproteinases and a disintegrin and metalloproteinases, [18F]FB-ML5, as a molecular probe for non-invasive MMP/ADAM-targeted imaging

  摘要：

  Background: Numerous clinical studies have shown a correlation between increased matrix metalloproteinase (MMP)/a disintegrin and metalloproteinase (ADAM) activity and poor outcome of cancer. Various MMP inhibitors (MMPIs) have been developed for therapeutic purposes in oncology. In addition, molecular imaging of MMP/ADAM levels in vivo would allow the diagnosis of tumors. We selected the dual inhibitor of MMPs and ADAMs, ML5, which is a hydroxamate-based inhibitor with affinities for many MMPs and ADAMs. ML5 was radiolabelled with F-18 and the newly obtained radiolabelled inhibitor was evaluated in vitro and in vivo.Materials and methods: ML5 was radiolabelled by direct acylation with N-succinimidyl-4-[F-18]fluorobenzoate ([F-18]SFB) for PET (positron emission tomography). The resulting radiotracer [F-18]FB-ML5 was evaluated in vitro in human bronchial epithelium 16HBE cells and breast cancer MCF-7 cells. The non-radioactive probe FB-ML5 and native ML5 were tested in a fluorogenic inhibition assay against MMP-2, -9, -12 and ADAM-17. The in vivo kinetics of [F-18]FB-ML5 were examined in a HT1080 tumor-bearing mouse model. Specificity of probe binding was examined by co-injection of 0 or 2.5 mg/kg ML5. Results: ML5 and FB-ML5 showed high affinity for MMP-2, -9, -12 and ADAM-17; indeed IC50 values were respectively 7.4 +/- 2.0, 19.5 +/- 2.8, 2.0 +/- 0.2 and 5.7 +/- 2.2 nM and 12.5 +/- 3.1, 31.5 +/- 13.7, 138.0 +/- 10.9 and 24.7 +/- 2.8 nM. Radiochemical yield of HPLC-purified [F-18]FB-ML5 was 13-16% (corrected for decay). Cellular binding of [F-18]FB-ML5 was reduced by 36.6% and 27.5% in MCF-7 and 16HBE cells, respectively, after co-incubation with 10 mu M of ML5. In microPET scans, HT1080 tumors exhibited a low and homogeneous uptake of the tracer. Tumors of mice injected with [F-18]FB-ML5 showed a SUVmean of 0.145 +/- 0.064 (n = 6) which decreased to 0.041 +/- 0.027 (n = 6) after target blocking (p < 0.05). Ex vivo biodistribution showed a rapid excretion through the kidneys and the liver. Metabolite assays indicated that the parent tracer represented 23.2 +/- 7.3% (n = 2) of total radioactivity in plasma, at 90 min post injection (p.i.).Conclusion: The nanomolar affinity MMP/ADAM inhibitor ML5 was successfully labelled with F-18. [F-18]FB-ML5 demonstrated rather low binding in ADAM-17 overexpressing cell lines. [F-18]FB-ML5 uptake showed significant reduction in the HT1080 tumor in vivo after co-injection of ML5. [F-18]FB-ML5 may be suitable for the visualization/quantification of diseases overexpressing simultaneously MMPs and ADAMs. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.11.013

文献信息

• [EN] CALPAIN MODULATORS AND METHODS OF PRODUCTION AND USE THEREOF<br/>[FR] MODULATEURS DE CALPAÏNE ET LEURS MÉTHODES DE PRODUCTION ET D'UTILISATION
  申请人：BLADE THERAPEUTICS INC

  公开号：WO2017156074A1

  公开（公告）日：2017-09-14

  The present technology relates to compounds, kits, compositions, and methods useful for the treatment of fibrotic disease. In some aspects, the present technology provides for treatment of various diseases or disorders associated or mediated, at least in part, by calpains, such as CAPN1, CAPN2, and/or CAPN9. The present technology is generally applicable to compounds which inhibit myofibroblast differentiation.

  这项技术涉及到用于治疗纤维化疾病的化合物、试剂盒、组合物和方法。在某些方面，这项技术提供了治疗与卡尔帕因（如CAPN1、CAPN2和/或CAPN9）至少部分相关或介导的各种疾病或疾病的方法。这项技术通常适用于抑制肌成纤维细胞分化的化合物。
• Peptide compound and its preparation
  申请人：Fujisawa Pharmaceutical Co. Ltd.

  公开号：US05284828A1

  公开（公告）日：1994-02-08

  Novel peptides of the formula (I") ##STR1## in which R.sup.1 is hydrogen or acyl, R.sup.2.sub.c is lower alkyl, R.sup.3.sub.c is optionally N-substituted indolylmethyl, R.sup.4 is hydrogen, lower alkyl, C.sub.6-10 ar(lower)alkyl, amino(lower)alkyl, protected amino (lower)alkyl, carboxy(lower)alkyl, protected carboxy(lower)alkyl or optionally substituted heterocyclic (lower)alkyl, R.sup.5 is carboxy, protected carboxy, carboxy(lower)alkyl or protected carboxy(lower)alkyl, R.sup.7 is hydrogen or lower alkyl, and A is --O--, --NH--, lower alkylamino or lower alkylene, or a pharmaceutically acceptable salt thereof are disclosed. Additionally, the preparation of such peptides is described. The peptides are used to treat endothelin mediated diseases such as hypertension.

  公开了具有以下结构的新型肽（I"）##STR1##其中R.sup.1是氢或酰基，R.sup.2.sub.c是较低的烷基，R.sup.3.sub.c是可选的N-取代吲哚甲基，R.sup.4是氢，较低的烷基，C.sub.6-10 ar(lower)alkyl，氨基（较低）烷基，受保护的氨基（较低）烷基，羧基（较低）烷基，受保护的羧基（较低）烷基，或者可选地取代的杂环（较低）烷基，R.sup.5是羧基，受保护的羧基，羧基（较低）烷基或受保护的羧基（较低）烷基，R.sup.7是氢或较低的烷基，A是--O--，--NH--，较低的烷基氨基或较低的亚烷基，或其药用可接受盐。此外，描述了这类肽的制备方法。这些肽被用于治疗由内皮素介导的疾病，如高血压。
• A peptide hydroxamate library for enrichment of metalloproteinases: towards an affinity-based metalloproteinase profiling protocol
  作者：Paul Geurink、Theo Klein、Michiel Leeuwenburgh、Gijs van der Marel、Henk Kauffman、Rainer Bischoff、Herman Overkleeft

  DOI：10.1039/b718352f

  日期：——

  A compound library of 96 enantiopure N-terminal succinyl hydroxamate functionalized peptides was synthesized on solid phase. All compounds were tested for their inhibitory potential towards MMP-9, MMP-12 and ADAM-17, which led to the identification of both broad spectrum inhibitors and metalloproteinase-selective ones. Eight potent and less potent inhibitors were immobilized on Sepharose beads and evaluated in solid-phase enrichment of active MMP-9, MMP-12 and ADAM-17. In addition, one of these inhibitors was used for solid-phase enrichment of endogenous ADAM-17 from a complex proteome (a lysate prepared from cultured A549 cells).

  在固相上合成了一个由 96 个对映体纯 N 端琥珀酰羟酰胺官能化肽组成的化合物库。测试了所有化合物对 MMP-9、MMP-12 和 ADAM-17 的抑制潜力，从而确定了广谱抑制剂和金属蛋白酶选择性抑制剂。在固相富集活性 MMP-9、MMP-12 和 ADAM-17 的过程中，对固定在 Sepharose 珠上的八种强效和弱效抑制剂进行了评估。此外，其中一种抑制剂还被用于固相富集复杂蛋白质组（由培养的 A549 细胞制备的裂解物）中的内源性 ADAM-17。
• Chemical Tools for Selective Activity Profiling of Endogenously Expressed MMP-14 in Multicellular Models
  作者：Neri Amara、Martina Tholen、Matthew Bogyo

  DOI：10.1021/acschembio.8b00562

  日期：2018.9.21

  targeting of MMPs by engineering a functionally silent cysteine mutation that enables highly specific covalent modification by a designed activity-based probe. Here, we describe the translation of that technology into a mouse model of breast cancer and subsequent demonstration of the utility of the approach for studies of MMP-14 activation in the tumor microenvironment. Using this approach, we find that MMP-14

  基质金属蛋白酶（MMPs）是锌依赖性内肽酶的一大家族，参与多种生理和病理学过程，特别是在癌症中。当前的成像和定量MMP活性的方法缺乏足够的选择性和时空分辨率，无法进行体内特定MMP功能的研究。以前，我们报道了通过设计功能性沉默的半胱氨酸突变来选择性靶向MMP的策略，该突变使半胱氨酸突变能够通过设计的基于活性的探针进行高度特异性的共价修饰。在这里，我们描述了将该技术翻译成乳腺癌的小鼠模型，并随后证明了该方法在肿瘤微环境中研究MMP-14激活的实用性。使用这种方法，我们发现MMP-14在晚期肿瘤中具有活性，并且主要与已被肿瘤细胞产生的特定信号分子（例如TGFβ）激活的基质细胞群相关。我们的数据证明了该方法在整个生物体中MMP功能研究中的适用性，并确定了肿瘤微环境中MMP-14活性的重要调控机制。
• Endothelin antagonists and their preparation
  申请人：Fujisawa Pharmaceutical Co., Ltd.

  公开号：US05538950A1

  公开（公告）日：1996-07-23

  A compound of the formula: ##STR1## in which R.sup.3 is hydrogen or lower alkyl, R.sup.4 is pyridyl (lower) alkyl; and R.sup.1, R.sup.2, R.sup.5 and A are defined in the description; or a pharmaceutically acceptable salt thereof, which have endothelin antagonistic activity.

  一种化合物的公式为：##STR1## 其中R.sup.3是氢或较低的烷基，R.sup.4是吡啶基（较低）烷基; R.sup.1，R.sup.2，R.sup.5和A在描述中有定义; 或其药学上可接受的盐，具有内皮素拮抗活性。