(2R,3S)-3-[formyl(hydroxy)amino]-2-(2-methylpropyl)-N-[(2S)-5-[[(E)-N'-nitrocarbamimidoyl]amino]-1-oxo-1-(1,3-thiazol-2-ylamino)pentan-2-yl]hexanamide

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 肽模拟物
• 英文名称: (2R,3S)-3-[formyl(hydroxy)amino]-2-(2-methylpropyl)-N-[(2S)-5-[[(E)-N'-nitrocarbamimidoyl]amino]-1-oxo-1-(1,3-thiazol-2-ylamino)pentan-2-yl]hexanamide
• 化学式: C₂₀H₃₄N₈O₆S
• 分子量: 514.606
• InChiKey: YKVNFNGMIAJYOQ-PMPSAXMXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  35
• 可旋转键数：
  15
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  236
• 氢给体数：
  5
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  (2R,3R)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutylhexanoic acid 在 N-甲基吗啉 、 氰基磷酸二乙酯 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 (2R,3S)-3-[formyl(hydroxy)amino]-2-(2-methylpropyl)-N-[(2S)-5-[[(E)-N'-nitrocarbamimidoyl]amino]-1-oxo-1-(1,3-thiazol-2-ylamino)pentan-2-yl]hexanamide
  参考文献：
  名称：

  Design of Selective and Soluble Inhibitors of Tumor Necrosis Factor-α Converting Enzyme (TACE)

  摘要：

  A program to improve upon the in vitro, in vivo, and physicochemical properties of N-hydroxyformamide TACE inhibitor GW 3333 (1) is described. Using the primary structure of pro-TNF-alpha, along with a homology model of the catalytic domain of TACE based on the X-ray diffraction coordinates of adamalysin, we synthesized N-hydroxyformamide TACE inhibitors containing a P2' arginine side chain. Introduction of nitro and sulfonyl electron-withdrawing groups covalently bound to the P2' guanidine moiety rendered the inhibitors electronically neutral at cellular pH and led to potent inhibition of TNF-alpha release from stimulated macrophages. Inhibitors containing these arginine mimetics were found to have increased solubility in simulated gastric fluid (SGF) relative to 1, allowing for the incorporation of lipophilic P1' side chains which had the effect of retaining potent TACE inhibition, but reducing potency against matrix metalloproteases (MMPs) thus increasing overall selectivity against MMP1, MMP3, and MMP9. Selected compounds showed good to excellent in vivo TNF inhibition when administered via subcutaneous injection. One inhibitor, 28a, with roughly 10x selectivity over MMPI and MMP3 and high solubility in SGF, was evaluated in the rat zymosan-induced pleuisy model of inflammation and found to inhibit zymosan-stimulated pleural TNF-alpha elevation by 30%.

  DOI：

  10.1021/jm0102654

文献信息

• UTILIZATION OF TACE INHIBITORS FOR THE TREATMENT OF ACNE
  申请人：AUBERT JÉRÔME

  公开号：US20100168089A1

  公开（公告）日：2010-07-01

  An in vitro method of screening for candidate compounds for the preventive or curative treatment of acne entails determination of the ability of a compound to inhibit the expression or the activity of TACE, and also to the administration of inhibitors of the expression or of the activity of this enzyme, in the treatment of acne.

  一种体外筛选预防或治疗痤疮候选化合物的方法，需要确定化合物抑制TACE（酶）表达或活性的能力，并且使用这种酶表达或活性的抑制剂进行痤疮治疗。
• Method of using a COX-2 inhibitor and a TACE inhibitors as a combination therapy
  申请人：Pharmacia Corporation

  公开号：US20040122011A1

  公开（公告）日：2004-06-24

  The present invention provides compositions and methods to treat, prevent or inhibit a neoplasia, a neoplasia-related disorder, pain, inflammation, an inflammatory-related disorder, a vaso-occlusive event or a vaso-occlusive-related disorder in a mammal using a combination of a COX-2 inhibitor and a TACE inhibitor.

  本发明提供了一种使用COX-2抑制剂和TACE抑制剂的组合物和方法，以治疗、预防或抑制哺乳动物中的肿瘤、肿瘤相关疾病、疼痛、炎症、炎症相关疾病、血管闭塞性事件或血管闭塞性相关疾病。
• Specific protease inhibitors and their use in cancer therapy
  申请人：GSF-FORSCHUNGSZENTRUM FÜR UMWELT UND GESUNDHEIT, GMBH

  公开号：EP1865001A1

  公开（公告）日：2007-12-12

  The present invention relates to a pharmaceutical composition comprising at least one inhibitor of EpCAM cleavage and at least one anti-EpCAM antibody, the use of least one inhibitor of EpCAM cleavage and at least one anti-EpCAM antibody for the manufacture of a medicament for the treatment and/or prevention of cancer, an in vitro method of inhibiting cancer by inhibiting cleavage of EpCAM, the use of a TACE inhibitor and/or a prese-nilin-2 inhibitor for inhibiting EpCAM cleavage, and a method of identifying a compound useful as an anti-cancer agent.

  本发明涉及一种药物组合物，该组合物包含至少一种EpCAM裂解抑制剂和至少一种抗EpCAM抗体；使用至少一种EpCAM裂解抑制剂和至少一种抗EpCAM抗体制造治疗和/或预防癌症的药物、一种通过抑制 EpCAM 的裂解来抑制癌症的体外方法，一种使用 TACE 抑制剂和/或 prese-nilin-2 抑制剂来抑制 EpCAM 裂解的方法，以及一种鉴定可用作抗癌剂的化合物的方法。
• SPECIFIC PROTEASE INHIBITORS AND THEIR USE IN CANCER THERAPY
  申请人：GSF-Forschungszentrum für Umwelt und Gesundheit GmbH

  公开号：EP2041181A1

  公开（公告）日：2009-04-01
• INHIBITEURS DE TACE DANS LE TRAITEMENT DE L'ACNE
  申请人：Galderma Research & Development

  公开号：EP2160606A2

  公开（公告）日：2010-03-10