Boc-Arg(Tos)-benzothiazol-2-yl | 179746-22-6

• 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: Boc-Arg(Tos)-benzothiazol-2-yl
• 英文别名: tert-butyl N-[(2S)-5-[[amino-[(4-methylphenyl)sulfonylamino]methylidene]amino]-1-(1,3-benzothiazol-2-yl)-1-oxopentan-2-yl]carbamate
• CAS: 179746-22-6
• 化学式: C₂₅H₃₁N₅O₅S₂
• 分子量: 545.684
• InChiKey: WNDNGJHWUWYLBA-IBGZPJMESA-N

物化性质

• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  37
• 可旋转键数：
  12
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  190
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  Boc-Arg(Tos)-benzothiazol-2-yl 在 甲醇 、 sodium tetrahydroborate 、 氢氟酸 、 戴斯-马丁氧化剂 、 苯甲醚 、 1-羟基苯并三唑一水物 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 RWJ-56423
  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：

  Boc-Arg(Tos)-N-methoxy-N-methylamide 、 2-苯并噻唑基锂 以 四氢呋喃 为溶剂， 生成 Boc-Arg(Tos)-benzothiazol-2-yl
  参考文献：
  名称：

  探测S1亚位点的有效凝血酶抑制剂：基于杂环活化羰基的三肽过渡态类似物。

  摘要：

  DOI：

  10.1021/jm9603274

文献信息

• 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
• Potent, Small-Molecule Inhibitors of Human Mast Cell Tryptase. Antiasthmatic Action of a Dipeptide-Based Transition-State Analogue Containing a Benzothiazole Ketone
  作者：Michael J. Costanzo、Stephen C. Yabut、Harold R. Almond,、Patricia Andrade-Gordon、Thomas W. Corcoran、Lawrence de Garavilla、Jack A. Kauffman、William M. Abraham、Rosario Recacha、Debashish Chattopadhyay、Bruce E. Maryanoff

  DOI：10.1021/jm030050p

  日期：2003.8.1

  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.
• Potent Thrombin Inhibitors That Probe the S₁‘ Subsite:  Tripeptide Transition State Analogues Based on a Heterocycle-Activated Carbonyl Group
  作者：Michael J. Costanzo、Bruce E. Maryanoff、Leonard R. Hecker、Mary R. Schott、Stephen C. Yabut、Han-Cheng Zhang、Patricia Andrade-Gordon、Jack A. Kauffman、Joan M. Lewis、Raman Krishnan、Alexander Tulinsky

  DOI：10.1021/jm9603274

  日期：1996.1.1