4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)benzonitrile | 486408-89-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 咪唑并嘧啶类
• 英文名称: 4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)benzonitrile
• 英文别名: 4-{[(2-Amino-6-Oxo-6,9-Dihydro-1h-Purin-8-Yl)sulfanyl]methyl}benzonitrile；4-[(2-amino-6-oxo-1,7-dihydropurin-8-yl)sulfanylmethyl]benzonitrile
• CAS: 486408-89-3
• 化学式: C₁₃H₁₀N₆OS
• 分子量: 298.328
• InChiKey: GWZOSZRSFBULCC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  145
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  对氰基溴化苄 、 8-mercaptoguanine 在 sodium hydroxide 作用下， 以 乙醇 为溶剂， 以73%的产率得到4-(((2-amino-6-oxo-6,9-dihydro-1H-purin-8-yl)thio)methyl)benzonitrile
  参考文献：
  名称：

  Structure-Based Design and Development of Functionalized Mercaptoguanine Derivatives as Inhibitors of the Folate Biosynthesis Pathway Enzyme 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from Staphylococcus aureus

  摘要：

  6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 angstrom upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors.

  DOI：

  10.1021/jm501417f

文献信息

• [EN] HETEROCYCLIC GTP CYCLOHYDROLASE 1 INHIBITORS FOR THE TREATMENT OF PAIN<br/>[FR] INHIBITEURS HÉTÉROCYCLIQUES DE LA GTP CYCLOHYDROLASE 1 POUR LE TRAITEMENT DE LA DOULEUR
  申请人：HERCULES TECHNOLOGY MAN CO V INC

  公开号：WO2011035009A1

  公开（公告）日：2011-03-24

  The present invention relates to the field of small molecule heterocyclic inhibitors of GTP cyclohydrolase (GCH-I), or a tautomer, prodrug, or pharmaceutically acceptable salt thereof. The invention also features pharmaceutical compositions of the compounds and the medical use of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, or neuropathic pain).

  本发明涉及小分子杂环抑制剂对GTP环化酶（GCH-I）的，或其互变异构体、前药或药用可接受盐。该发明还涉及这些化合物的药物组合物以及这些化合物用于治疗或预防疼痛（例如炎症性疼痛、伤害性疼痛、功能性疼痛或神经病理性疼痛）的医疗用途。
• Structure-Based Design and Development of Functionalized Mercaptoguanine Derivatives as Inhibitors of the Folate Biosynthesis Pathway Enzyme 6-Hydroxymethyl-7,8-dihydropterin Pyrophosphokinase from <i>Staphylococcus aureus</i>
  作者：Matthew L. Dennis、Sandeep Chhabra、Zhong-Chang Wang、Aaron Debono、Olan Dolezal、Janet Newman、Noel P. Pitcher、Raphael Rahmani、Ben Cleary、Nicholas Barlow、Meghan Hattarki、Bim Graham、Thomas S. Peat、Jonathan B. Baell、James D. Swarbrick

  DOI：10.1021/jm501417f

  日期：2014.11.26

  6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (HPPK), an enzyme from the folate biosynthesis pathway, catalyzes the pyrophosphoryl transfer from ATP to 6-hydroxymethyl-7,8-dihydropterin and is a yet-to-be-drugged antimicrobial target. Building on our previous discovery that 8-mercaptoguanine (8MG) is an inhibitor of Staphylococcus aureus HPPK (SaHPPK), we have identified and characterized the binding of an S8-functionalized derivative (3). X-ray structures of both the SaHPPK/3/cofactor analogue ternary and the SaHPPK/cofactor analogue binary complexes have provided insight into cofactor recognition and key residues that move over 30 angstrom upon binding of 3, whereas NMR measurements reveal a partially plastic ternary complex active site. Synthesis and binding analysis of a set of analogues of 3 have identified an advanced new lead compound (11) displaying >20-fold higher affinity for SaHPPK than 8MG. A number of these exhibited low micromolar affinity for dihydropteroate synthase (DHPS), the adjacent, downstream enzyme to HPPK, and may thus represent promising new leads to bienzyme inhibitors.
• Heterocyclic GTP Cyclohydrolase 1 Inhibitors For the Treatment of Pain
  申请人：Blagg Julian

  公开号：US20120252791A1

  公开（公告）日：2012-10-04

  The present invention relates to the field of small molecule heterocyclic inhibitors of GTP cyclohydrolase (GCH-I), or a tautomer, prodrug, or pharmaceutically acceptable salt thereof. The invention also features pharmaceutical compositions of the compounds and the medical use of these compounds for the treatment or prevention of pain (e.g., inflammatory pain, nociceptive pain, functional pain, or neuropathic pain).