2-(5-chloro-2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetic acid | 308845-87-6

• 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: 2-(5-chloro-2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetic acid
• 英文别名: 3-(2-phenylethylamino)-5-chloro-6-phenyl-1-methylenecarboxypyrazinone；2-[5-Chloro-2-oxo-6-phenyl-3-(2-phenylethylamino)pyrazin-1-yl]acetic acid
• CAS: 308845-87-6
• 化学式: C₂₀H₁₈ClN₃O₃
• 分子量: 383.834
• InChiKey: PFTIZQWAPGXESI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  82
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(5-chloro-2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetic acid 在 palladium on activated charcoal polymer-bound carbodiimide reagent 、 氢气 、 1-羟基苯并三唑 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、68.95 kPa 条件下， 生成 N-(3-Carbamimidoyl-benzyl)-2-(2-oxo-3-phenethylamino-6-phenyl-2H-pyrazin-1-yl)-acetamide
  参考文献：
  名称：

  Design, Parallel Synthesis, and Crystal Structures of Pyrazinone Antithrombotics as Selective Inhibitors of the Tissue Factor VIIa Complex

  摘要：

  Structure-based drug design (SBDD) and polymer-assisted solution-phase (PASP) library synthesis were used to develop a series of pyrazinone inhibitors of the Tissue Factor/Factor Vlla (TF/VIIa) complex. The crystal structure of a tripeptide-alpha-ketothiazole complexed with TF/VIIa was utilized in a docking experiment to identify the pyrazinone core as a starting scaffold. The pyrazinone core could orient the substituents in the correct spatial arrangement to probe the S-1, S-2, and S-3 pockets of the enzyme. A multistep PASP library synthesis was designed to prepare the substituted pyrazinones varying the P-1, P-2, and P-3 moieties. Hundreds of pyrazinone TF/VIIa inhibitors were prepared and tested in several serine protease enzyme assays involved in the coagulation cascade. The inhibitors exhibited modest activity on TF/ VIIa with excellent selectivity over thrombin (Ha) and Factor Xa. The structure-activity relationship of the pyrazinone inhibitors will be discussed and X-ray crystal structures of selected compounds complexed with the TF/VIIa enzyme will be described. This study ultimately led to the synthesis of compound 34, which exhibited 16 nM (IC50) activity on TF/VIIa with >6250x selectivity vs Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical, intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a nonhuman primate model of electrolytic-induced arterial thrombosis.

  DOI：

  10.1021/jm030131l
• 作为产物：
  描述：

  benzyl (cyano(phenyl)methyl)glycinate hydrochloride 在 盐酸 、 氢氧化钾 作用下， 以 四氢呋喃 、 甲醇 、 水 、 乙酸乙酯 、 邻二氯苯 为溶剂， 反应 39.0h， 生成 2-(5-chloro-2-oxo-3-(phenethylamino)-6-phenylpyrazin-1(2H)-yl)acetic acid
  参考文献：
  名称：

  Substituted polycyclic aryl and heteroaryl pyrazinones useful for selective inhibition of the coagulation cascade

  摘要：

  这项发明涉及替代多环芳基和杂环芳基吡唑酮化合物，可用作凝血级联中丝氨酸蛋白酶的抑制剂，以及用于治疗和预防包括冠状动脉和脑血管疾病在内的各种血栓症状的抗凝治疗的化合物、组合物和方法。

  公开号：

  US06664255B1

文献信息

• [EN] MASP-2 INHIBITORS AND METHODS OF USE<br/>[FR] INHIBITEURS DE MASP-2 ET PROCÉDÉS D'UTILISATION
  申请人：OMEROS CORP

  公开号：WO2021113686A1

  公开（公告）日：2021-06-10

  The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.

  本公开提供了具有MASP-2抑制活性的化合物，这些化合物的组合物以及制备和使用这些化合物的方法。
• Structure-based drug design of pyrazinone antithrombotics as selective inhibitors of the tissue factor VIIa complex
  作者：Michael S. South、Brenda L. Case、Rhonda S. Wood、Darin E. Jones、Michael J. Hayes、Thomas J. Girard、Rhonda M. Lachance、Nancy S. Nicholson、Michael Clare、Anna M. Stevens、Roderick A. Stegeman、William C. Stallings、Ravi G. Kurumbail、John J. Parlow

  DOI：10.1016/s0960-894x(03)00410-4

  日期：2003.7

  Structure-based drug design coupled with polymer-assisted solution-phase library synthesis was utilized to develop a series of pyrazinone inhibitors of the tissue factor/Factor Vila complex. The crystal structure of a tri-peptide ketothiazole complexed with TF/VIIa was utilized in a docking experiment that identified a benzyl-substituted pyrazinone as a P-2 surrogate for the tri-peptide. A 5-step PASP library synthesis of these aryl-substituted pyrazinones was developed. The sequence allows for attachment of a variety of P-1 and P-3 moieties, which led to synthesis pyrazinone 23. Compound 23 exhibited 16 nM IC50 against TF/VIIa with > 6250x selectivity versus Factor Xa and thrombin. This potent and highly selective inhibitor of TF/VIIa was chosen for preclinical intravenous proof-of-concept studies to demonstrate the separation between antithrombotic efficacy and bleeding side effects in a primate model of thrombosis. (C) 2003 Elsevier Science Ltd. All rights reserved.
• SUBSTITUTED POLYCYCLIC ARYL AND HETEROARYL PYRAZINONES USEFUL FOR SELECTIVE INHIBITION OF THE COAGULATION CASCADE
  申请人：Pharmacia Corporation

  公开号：EP1202975A1

  公开（公告）日：2002-05-08
• MASP-2 INHIBITORS AND METHODS OF USE
  申请人：Omeros Corporation

  公开号：US20210179612A1

  公开（公告）日：2021-06-17

  The present disclosure provides, inter alia, compounds with MASP-2 inhibitory activity, compositions of such compounds, and methods of making and using such compounds.
• US6664255B1
  申请人：——

  公开号：US6664255B1

  公开（公告）日：2003-12-16