RWJ-56423 | 287182-50-7

• 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: RWJ-56423
• 英文别名: (2S,4R)-1-acetyl-N-[(1S)-4-[(aminoiminomethyl)amino]-1-(2-benzothiazolylcarbonyl)butyl]-4-hydroxy-2-pyrrolidinecarboxamide；(2S,4R)-1-acetyl-N-[(1S)-1-(2-benzothiazolyl-carbonyl)-4-[[imino(amino)methyl]amino]butyl]-4-hydroxypyrrolidine-2-carboxamide；(2S,4R)-1-acetyl-N-[(1S)-1-(2-benzothiazolylcarbonyl)-4-[[imino(amino)methyl]-amino]butyl]-4-hydroxypyrrolidine-2-carboxamide；(2S,4R)-1-acetyl-N-[(2S)-1-(1,3-benzothiazol-2-yl)-5-(diaminomethylideneamino)-1-oxopentan-2-yl]-4-hydroxypyrrolidine-2-carboxamide
• CAS: 287182-50-7
• 化学式: C₂₀H₂₆N₆O₄S
• 分子量: 446.53
• InChiKey: VXDAVYUFYPFGDX-SNPRPXQTSA-N

物化性质

• 密度：
  1.53±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0
• 重原子数：
  31
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.45
• 拓扑面积：
  192
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  RWJ-56423 在 硫酸 作用下， 以 水 、 异丙醇 为溶剂， 反应 25.0h， 生成 (2S,4R)-1-acetyl-N-[(1S)-4-[(aminoiminomethyl)amino]-1-(2-benzothiazolylcarbonyl)butyl]-4-hydroxy-2-pyrrolidinecarboxamide sulfate salt
  参考文献：
  名称：

  Process for preparing peptidyl heterocyclic ketone derivatives

  摘要：

  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。

  公开号：

  US20050059607A1
• 作为产物：
  描述：

  Ac-Hyp(OBzl)-OMe 在 lithium hydroxide 、 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 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 27.5h， 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

文献信息

• [EN] PEPTIDYL HETEROCYCLIC KETONES USEFUL AS TRYPTASE INHIBITORS<br/>[FR] PEPTIDYLCETONES HETEROCYCLIQUES INHIBITRICES DE LA TRYPTASE
  申请人：ORTHO MCNEIL PHARM INC

  公开号：WO2000044733A1

  公开（公告）日：2000-08-03

  The present invention relates to a series of peptidyl heterocyclic ketones which are inflammatory cell serine protease inhibitors and their compositions and methods for the prevention and treatment of a variety of immunomediated inflammatory disorders. More particularly, these compounds are potent and selective inhibitors of tryptase and are therefore effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis.

  本发明涉及一系列肽基杂环酮，它们是炎症细胞丝氨酸蛋白酶抑制剂及其组合物和预防和治疗各种免疫介导的炎症性疾病的方法。更具体地说，这些化合物是强效和选择性的替普汀酶抑制剂，因此对于预防和治疗与呼吸道有关的炎症性疾病，如哮喘和过敏性鼻炎，具有有效性。
• [EN] PEPTIDYL HETEROCYCLIC KETONE DERIVATIVES AND PREPARATION PROCESSES<br/>[FR] DERIVES CETONES HETEROCYCLIQUES PEPTIDYLIQUES ET PROCEDES DE DE PREPARATION
  申请人：JANSSEN PHARMACEUTICA NV

  公开号：WO2005023804A1

  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.

  本发明涉及一种制备通式（I）中所有变量如此定义的肽杂环酮的新工艺。本发明还涉及新的药物盐及其制备工艺。通式（I）中的肽杂环酮是一种有效且选择性的胰蛋白酶抑制剂，可用于治疗和预防与呼吸道有关的炎症性疾病，如哮喘和过敏性鼻炎。
• Peptidyl heterocyclic ketones useful as tryptase inhibitors
  申请人：——

  公开号：US20030008829A1

  公开（公告）日：2003-01-09

  The present invention relates to a series of peptidyl heterocyclic ketones which are inflammatory cell serine protease inhibitors and their compositions and methods for the prevention and treatment of a variety of immunomediated inflammatory disorders. More particularly, these compounds are potent and selective inhibitors of tryptase and are therefore effective for the prevention and treatment of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis.

  本发明涉及一系列肽杂环酮，它们是炎症细胞丝氨酸蛋白酶抑制剂及其组合物和用于预防和治疗各种免疫介导的炎症性疾病的方法。更具体地说，这些化合物是强效且选择性的组胺酶抑制剂，因此对于预防和治疗与呼吸道相关的炎症性疾病，如哮喘和过敏性鼻炎，非常有效。
• Advanced drug development and manufacturing
  申请人：Los Alamos National Security, LLC

  公开号：EP2511844A2

  公开（公告）日：2012-10-17

  There is described an apparatus for measuring protein characteristics comprising an X-ray fluorescence (XRF) spectrometer comprising a source of polychromatic X-rays, an X-ray detector, a protein, a molecule that has been exposed to and at least weakly binds to the protein, a plurality of X-ray fluorescence signal data obtained by irradiating chemical elements in the protein and molecule with the polychromatic X-rays and a security system for maintaining records for the data from the plurality of X-ray fluorescence signal measurements. There is also described an x-ray microscope for measuring a sample.

  描述了一种测量蛋白质特性的仪器，该仪器包括一个 X 射线荧光 (XRF) 光谱仪，其中包括一个多色 X 射线源、一个 X 射线探测器、一个蛋白质、一个已暴露于该蛋白质并至少与该蛋白质弱结合的分子、通过用多色 X 射线照射蛋白质和分子中的化学元素而获得的多个 X 射线荧光信号数据，以及一个用于维护多个 X 射线荧光信号测量数据记录的安全系统。此外，还介绍了一种用于测量样品的 X 射线显微镜。
• Opioid compositions resistant to overdose and abuse
  申请人：Elysium Therapeutics, Inc.

  公开号：US10335406B2

  公开（公告）日：2019-07-02

  The invention provides pharmaceutical compositions comprising macromolecular gastrointestinal enzyme-labile opioid prodrugs, co-formulated with small-molecule and/or macromolecular gastrointestinal enzyme inhibitors. The macromolecular constructs are minimally absorbed from the GI tract, and can produce non-linear pharmacokinetic profiles of the delivered opioid agonist following oral ingestion. An optional macromolecular opioid antagonist may also be present in compositions of the invention to discourage tampering by potential abusers.

  本发明提供了由大分子胃肠道酶抑制阿片类原药与小分子和/或大分子胃肠道酶抑制剂共同配制而成的药物组合物。大分子构建物从胃肠道的吸收率极低，口服后可产生所输送阿片类激动剂的非线性药代动力学特征。本发明的组合物中还可加入一种可选的大分子阿片拮抗剂，以防止潜在的滥用者篡改。