(S)-benzyl(1-((cyanomethyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate

• 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: (S)-benzyl(1-((cyanomethyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate
• 英文别名: Cbz-Leu-NHCH2CN；benzyl (S)-1-cyanomethylcarbamoyl-3-methylbutylcarbamate；benzyl N-[(2S)-1-(cyanomethylamino)-4-methyl-1-oxopentan-2-yl]carbamate
• 化学式: C₁₆H₂₁N₃O₃
• 分子量: 303.361
• InChiKey: UFXQLUZNMRVTPU-AWEZNQCLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  91.2
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-benzyl(1-((cyanomethyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate 、 [Ru(tris(2-pyridylmethyl)amine)(H2O)2](CF3SO3)2 以 乙醇 为溶剂， 反应 24.0h， 以501 mg的产率得到
  参考文献：
  名称：

  Nitrile-containing enzyme inhibitors and ruthenium complexes thereof

  摘要：

  这项发明提供了与钌化合物结合的含腈基蛋白酶抑制剂。这些腈基蛋白酶抑制剂与钌化合物结合后形成失活的抑制剂，可以通过光照等方式被释放到表面或部位进行激活。该发明还提供了将蛋白酶抑制剂传递给受试者以治疗癌症等疾病的方法。

  公开号：

  US20140100173A1
• 作为产物：
  描述：

  N-苄氧羰基-L-亮氨酸 在 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 27.0h， 生成 (S)-benzyl(1-((cyanomethyl)amino)-4-methyl-1-oxopentan-2-yl)carbamate
  参考文献：
  名称：

  Design and Synthesis of Tri-Ring P₃ Benzamide-Containing Aminonitriles as Potent, Selective, Orally Effective Inhibitors of Cathepsin K

  摘要：

  We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P-2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone). The best compound in this series, 39n (CRA-013783/ L-006235), was orally bioavailable in rats, with a terminal half-life of over 3 h. 39n was dosed orally in ovariectomized rhesus monkeys once per day for 7 days. Collagen breakdown products were reduced by up to 76% dose-dependently. Plasma concentrations of 39n above the bone resorption IC50 after 24 h indicated a correlation between functional cellular and in vivo assays. Inhibition of collagen breakdown by cathepsin K inhibitors suggests this mechanism of action may be useful in osteoporosis and other indications involving bone resorption.

  DOI：

  10.1021/jm058198r

文献信息

• Interaction of Papain-like Cysteine Proteases with Dipeptide-Derived Nitriles
  作者：Reik Löser、Klaus Schilling、Elke Dimmig、Michael Gütschow

  DOI：10.1021/jm050686b

  日期：2005.12.1

  were introduced, and systematic fluorine, bromine, and phenyl scans for phenylalanine in the P2 position were performed. Moreover, the N-terminal protection was varied. Kinetic investigations were carried out with cathepsin L, S, and K as well as papain. Changes in the backbone structure of the parent N-(tert-butoxycarbonyl)-phenylalanyl-glycine-nitrile (16), such as the introduction of an R-configured

  制备一系列44个在P2位具有各种氨基酸和在P1位具有甘氨酸的二肽腈，并将其评估为半胱氨酸蛋白酶的抑制剂。关于P2-S2相互作用对酶抑制剂复合物形成的重要贡献，重点是将结构多样性引入P2侧链。引入了非蛋白氨基酸，并进行了系统的氟，溴和苯基扫描，以检测P2位置的苯丙氨酸。而且，N-末端保护是多种多样的。使用组织蛋白酶L，S和K以及木瓜蛋白酶进行动力学研究。母体N-（叔丁氧羰基）-苯丙氨酰基-甘氨酸-腈的骨架结构变化（16），例如将R构型的氨基酸或氮杂氨基酸引入P2以及P1氮的甲基化，会导致亲和力的急剧下降。示例性地，16的氰基被醛或甲基酮官能团取代。关于靶酶的底物特异性，讨论了构效关系。
• Novel compounds and compositions as protease inhibitors
  申请人：AXYS PHARMACEUTICALS, INC.

  公开号：US20020086996A1

  公开（公告）日：2002-07-04

  The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

  本发明涉及一种新颖的N-氰甲基酰胺，它们是半胱氨酸蛋白酶抑制剂，以及它们的药用盐和N-氧化物，它们作为治疗剂的用途以及它们的制备方法。
• New Ru(<scp>ii</scp>) complex for dual photochemotherapy: release of cathepsin K inhibitor and¹O₂production
  作者：Thomas N. Rohrabaugh、Kelsey A. Collins、Congcong Xue、Jessica K. White、Jeremy J. Kodanko、Claudia Turro

  DOI：10.1039/c8dt00876k

  日期：——

  properties of 1 were compared with those of [Ru(tpy)(bpy)(Cbz-Leu-NHCH2CN)]2+ (2, bpy = 2,2′-bipyridine), [Ru(tpy)(dppn)(CH3CN)]2+ (3), and [Ru(tpy)(bpy)(CH3CN)]2+ (4) to evaluate the effect of the release of the Cbz-Leu-NHCH2CN inhibitor relative to the CH3CN ligand, as well as the role of dppn as the bidentate ligand for 1O2 production instead of bpy. Nanosecond transient absorption spectroscopy

  一种新的络合物[Ru（tpy）（dppn）（Cbz-Leu-NHCH 2 CN）] 2+（1，tpy = 2,2'：6'，2''-叔吡啶，dppn =苯并[ i ]双吡啶合成了[3,2- a：2'，3'- c ]吩嗪），并对其光化学性质进行了研究。这种复杂的经历光致的CBZ-LEU-NHCH的2 CN配体，组织蛋白酶K抑制剂已知的，其中一个量子产率，Φ 450，在水0.0012（4）（λ IRR = 450纳米）。此外，1在可见光照射敏化生产单重态氧的量子产率，Φ Δ在CH，0.64（3）3哦。将1的光物理性质与[Ru（tpy）（bpy）（Cbz-Leu-NHCH 2 CN）] 2+（2，bpy = 2,2'-联吡啶），[Ru（tpy）（dppn ）（CH 3 CN）] 2+（3）和[Ru（tpy）（bpy）（CH 3 CN）] 2+（4）以评估Cbz-Leu-NHCH 2 CN抑制剂释放的影响相对于CH
• Inhibition of Cathepsin Activity in a Cell-Based Assay by a Light-Activated Ruthenium Compound
  作者：Tomasz Respondek、Rajgopal Sharma、Mackenzie K. Herroon、Robert N. Garner、Jessica D. Knoll、Eric Cueny、Claudia Turro、Izabela Podgorski、Jeremy J. Kodanko

  DOI：10.1002/cmdc.201400081

  日期：2014.6

  Light‐activated inhibition of cathepsin activity was demonstrated in a cell‐based assay. Inhibitors of cathepsin K, Cbz‐Leu‐NHCH2CN (2) and Cbz‐Leu‐Ser(OBn)‐CN (3), were caged within the complexes cis‐[Ru(bpy)2(2)2]Cl2 (4) and cis‐[Ru(bpy)2(3)2](BF4)2 (5) (bpy=2,2′‐bipyridine) as 1:1 mixtures of Δ and Λ stereoisomers. Complexes 4 and 5 were characterized by 1H NMR, IR, and UV/Vis spectroscopies and

  在基于细胞的测定中证明了组织蛋白酶活性的光激活抑制。组织蛋白酶 K 抑制剂 Cbz-Leu-NHCH 2 CN ( 2 ) 和 Cbz-Leu-Ser(OBn)-CN ( 3 ) 被笼在复合物cis -[Ru(bpy) 2 ( 2 ) 2 ]Cl 2内( 4 ) 和顺式‐[Ru(bpy) 2 ( 3 ) 2 ](BF 4 ) 2 ( 5 ) (bpy=2,2′-联吡啶)作为Δ和Λ立体异构体的1:1混合物。配合物4和5通过1 H NMR、IR、UV/Vis 光谱和电喷雾质谱进行了表征。光化学实验证实，在可见光照射15分钟后， 4会释放出两个2分子，而3分子和5分子的释放则需要更长的照射时间。在光照和黑暗条件下用4和5对纯化的组织蛋白酶 K 进行的 IC 50测定证实，在可见光照射下，抑制作用分别增强了 35 倍至 88 倍。通过 MTT 测定，浓度高达 10 μM时，在骨髓巨噬细胞 (BMM)
• Compounds and compositions as protease inhibitors
  申请人：Axys Pharmaceuticals, Inc.

  公开号：US06593327B2

  公开（公告）日：2003-07-15

  The present invention relates to novel N-cyanomethyl amides which are cysteine protease inhibitors, the pharmaceutically acceptable salts and N-oxides thereof, their uses as therapeutic agents and the methods of their making.

  本发明涉及一种新型N-氰甲基酰胺，它们是半胱氨酸蛋白酶抑制剂，其药学上可接受的盐和N-氧化物，以及它们作为治疗剂的用途和制备方法。