[(1S)-1-(2-benzothiazolylcarbonyl)-4-[[imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester | 201006-62-4

• 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: [(1S)-1-(2-benzothiazolylcarbonyl)-4-[[imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester
• 英文别名: BocHN-Arg(Mtr)ketobenzothiazole；Boc-Arg(Mtr)-benzothiazol-2-yl；tert-butyl N-[(2S)-5-[[amino-[(4-methoxy-2,3,6-trimethylphenyl)sulfonylamino]methylidene]amino]-1-(1,3-benzothiazol-2-yl)-1-oxopentan-2-yl]carbamate
• CAS: 201006-62-4
• 化学式: C₂₈H₃₇N₅O₆S₂
• 分子量: 603.764
• InChiKey: LRLLROPLLQOOOE-FQEVSTJZSA-N

物化性质

• 熔点：
  227.22 °C
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.9
• 重原子数：
  41
• 可旋转键数：
  13
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  199
• 氢给体数：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  [(1S)-1-(2-benzothiazolylcarbonyl)-4-[[imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester 在 甲醇 、 sodium tetrahydroborate 、 对甲苯磺酸 、 1-羟基苯并三唑一水物 、 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 为溶剂， 反应 7.0h， 生成 (2S,4R)-1-acetyl-N-((2S)-1-(benzo[d]thiazol-2-yl)-1-hydroxy-5-(3-((4-methoxy-2,3,6-trimethylphenyl)sulfonyl)guanidino)pentan-2-yl)-4-hydroxypyrrolidine-2-carboxamide
  参考文献：
  名称：

  Potent, Small-Molecule Inhibitors of Human Mast Cell Tryptase. Antiasthmatic Action of a Dipeptide-Based Transition-State Analogue Containing a Benzothiazole Ketone

  摘要：

  Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a K-i value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (K-i = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-Angstrom resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness.

  DOI：

  10.1021/jm030050p
• 作为产物：
  描述：

  tert-butyl (S)-1-(methoxy(methyl)amino)-5-(3-(4-methoxy-2,3,6-trimethylphenylsulfonyl)guanidino)-1-oxopentan-2-ylcarbamate 在 正丁基锂 、 水 、 氯化铵 作用下， 以 四氢呋喃 、 hexanes 为溶剂， 反应 16.75h， 生成 [(1S)-1-(2-benzothiazolylcarbonyl)-4-[[imino[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]methyl]amino]butyl]carbamic acid 1,1-dimethylethyl ester
  参考文献：
  名称：

  Compounds and Compositions as Channel Activating Protease Inhibitors

  摘要：

  该发明提供了化合物及其药物组合物，这些化合物用于调节通道激活蛋白酶，以及使用这些化合物来治疗、改善或预防与通道激活蛋白酶相关的疾病的方法，包括但不限于前列腺素、PRSS22、TMPRSS11（例如，TMPRSS11B，TMPRSS11E）、TMPRSS2、TMPRSS3、TMPRSS4（MTSP-2）、膜联蛋白（MTSP-1）、CAP2、CAP3、胰蛋白酶、组织蛋白酶A或中性粒细胞弹性蛋白酶。

  公开号：

  US20070276002A1

文献信息

• [EN] INHIBITORS OF GROWTH FACTOR ACTIVATION ENZYMES<br/>[FR] INHIBITEURS D'ENZYMES D'ACTIVATION DE FACTEUR DE CROISSANCE
  申请人：UNIV WASHINGTON

  公开号：WO2016144654A1

  公开（公告）日：2016-09-15

  The present invention generally relates to compounds that are useful for inhibiting one or more of hepatocyte growth factor activator, matriptase, hepsin, Factor Xa, or thrombin. The present invention also relates to various methods of using the inhibitor compounds including treating a malignancy, a pre-malignant condition, or cancer by administering an effective amount of the inhibitor to a subject in need thereof.

  本发明通常涉及对抑制肝细胞生长因子激活剂、麦曲丝蛋白、赫普星、Xa因子或凝血酶等的化合物有用的化合物。本发明还涉及使用抑制剂化合物的各种方法，包括通过向需要的受试者施用有效量的抑制剂来治疗恶性肿瘤、癌前病变或癌症。
• Process for preparing peptidyl heterocyclic ketone derivatives
  申请人：Breslav Michael

  公开号：US20050059607A1

  公开（公告）日：2005-03-17

  The present invention relates to novel processes for the preparation of peptidyl heterocyclic ketones of the general formula (I) wherein all variables are as herein defined. The present invention further relates to novel pharmaceutical salts and processes for their preparation. The peptidyl heterocyclic ketones of formula (I) are potent and selective inhibitors of tryptase, useful for the treatment and prevention of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis.

  本发明涉及一种新型方法，用于制备一般公式（I）中的肽杂环酮，其中所有变量如本文所定义。本发明还涉及新型药用盐和其制备方法。公式（I）中的肽杂环酮是三肽酶的强效和选择性抑制剂，可用于治疗和预防与呼吸道相关的炎症性疾病，如哮喘和过敏性鼻炎。
• In-Depth Study of Tripeptide-Based α-Ketoheterocycles as Inhibitors of Thrombin. Effective Utilization of the S₁‘ Subsite and Its Implications to Structure-Based Drug Design
  作者：Michael J. Costanzo、Harold R. Almond、Leonard R. Hecker、Mary R. Schott、Stephen C. Yabut、Han-Cheng Zhang、Patricia Andrade-Gordon、Thomas W. Corcoran、Edward C. Giardino、Jack A. Kauffman、Joan M. Lewis、Lawrence de Garavilla、Barbara J. Haertlein、Bruce E. Maryanoff

  DOI：10.1021/jm0303857

  日期：2005.3.1

  structures of the ternary complexes 3-thrombin-hirugen and 4-thrombin-hirugen depict novel interactions in the S(1)' region, with the benzothiazole ring forming a hydrogen bond with His-57 and an aromatic stacking interaction with Trp-60D of thrombin's insertion loop. The benzothiazole ring of 3 displaces the Lys-60F side chain into a U-shaped gauche conformation, whereas the benzothiazole carboxylate

  凝血酶抑制剂由于其抗凝和抗血栓形成作用而可能在医学上有用。我们基于d-Phe-Pro-Arg以及相关的凝血酶活性位点识别基序合成和评估了各种杂环活化的酮，作为候选抑制剂。基于肽的α-酮杂环通常通过亚氨酸酯或Weinreb酰胺途径制备（方案1和2），事实证明后者更为普遍。通常测定测试化合物对人α-凝血酶和牛胰蛋白酶的抑制作用。从基于结构的设计角度来看，杂环允许人们探索和调节凝血酶S1'亚位点内的相互作用。优选的α-酮杂环是富含pi的2取代的吡咯，在带有酮基的碳原子的附近至少有两个杂原子，优选的凝血酶抑制剂是2-酮基苯并噻唑3，其有效K（i）值为0.2 nM，约为1。选择性比胰蛋白酶高15倍。2-酮苯并噻唑13表现出极强的凝血酶抑制作用（K（i）= 0.000 65 nM;缓慢紧密结合）。几个α-酮杂环化合物的凝血酶K（i）值在0.1-400 nM范围内。在温和的碱性条件下，α-酮杂环的“ A
• Structure-based design, synthesis, and biological evaluation of Leu-Arg dipeptide analogs as novel hepsin inhibitors
  作者：Hongmok Kwon、YunHye Kim、Kieung Park、Soo An Choi、Sang-Hyun Son、Youngjoo Byun

  DOI：10.1016/j.bmcl.2015.12.023

  日期：2016.1

  metastasis. Starting from the reported tetrapeptide hepsin inhibitor Ac-KQLR-ketothiazole (kt) (1), we investigated the minimal structural requirements for hepsin inhibitory activity by truncating amino acids at the N-terminus. The kt and ketobenzothiazole (kbt) dipeptide analogs Ac-LR-kt (3) and Ac-LR-kbt (15) were found to be potent hepsin inhibitors, exhibiting Ki values of 22nM and 3nM, respectively.

  肝素是一种II型跨膜丝氨酸蛋白酶，是一种有吸引力的蛋白质，可作为前列腺癌的潜在治疗和诊断生物标志物，因为它在前列腺癌中高度上调并促进进展和转移。从已报道的四肽肝素抑制剂Ac-KQLR-酮噻唑（kt）（1）开始，我们通过在N端截短氨基酸，研究了肝素抑制活性的最低结构要求。发现kt和酮基苯并噻唑（kbt）二肽类似物Ac-LR-kt（3）和Ac-LR-kbt（15）是有效的肝素抑制剂，其Ki值分别为22nM和3nM。目前的工作表明，含LR的二肽分子可用作开发新型肝素抑制剂的先导化合物。
• Analysis of Subpocket Selectivity and Identification of Potent Selective Inhibitors for Matriptase and Matriptase-2
  作者：Dominic Duchêne、Eloïc Colombo、Antoine Désilets、Pierre-Luc Boudreault、Richard Leduc、Eric Marsault、Rafael Najmanovich

  DOI：10.1021/jm5015633

  日期：2014.12.11

  We studied the factors affecting the selectivity of peptidomimetic inhibitors of the highly homologous proteases matriptase and matriptase-2 across subpockets using docking simulations. We observed that the farther away a subpocket is located from the catalytic site, the more pronounced its role in selectivity. As a result of our exhaustive virtual screening, we biochemically validated novel potent and selective inhibitors of both enzymes.