2,4-diamino-6-bromomethylpteridine*HBr*2-hydroxypropane

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 蝶啶及其衍生物
• 英文名称: 2,4-diamino-6-bromomethylpteridine*HBr*2-hydroxypropane
• 英文别名: 6-(Bromomethyl)pteridine-2,4-diamine;propan-2-ol;hydrobromide
• 化学式: BrH*C₃H₈O*C₇H₇BrN₆
• 分子量: 396.085
• InChiKey: MLEADWANIYIVBP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.44
• 重原子数：
  19
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  124
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  2,4-diamino-6-bromomethylpteridine*HBr*2-hydroxypropane 在 4-二甲氨基吡啶 、 氨 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 2,4-bis-isobutyroylamino-6-isobutyroylaminomethylpteridine
  参考文献：
  名称：

  Inhibition of Neuronal Nitric Oxide Synthase by 4-Amino Pteridine Derivatives:  Structure−Activity Relationship of Antagonists of (6R)-5,6,7,8-Tetrahydrobiopterin Cofactor

  摘要：

  The family of nitric oxide synthases (NOS) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in the pathophysiology of septic shock and inflammatory and neurodegenerative disease states. NOS can be maximally activated by the ubiquitous cofactor, (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip), and antagonists of H(4)Bip may be of therapeutic importance to inhibit pathologically high NO formation. The 4-amino substituted analogue of H(4)Bip was reported to be a potent NOS inhibit-or. Therefore, we developed a series of novel 4-amino pteridine derivatives, antipterins, to pharmacologically target the neuronal isoform of nitric oxide synthase (NOS-I). To functionally characterize the pterin/anti-pterin interaction and establish a structure-activity relationship (SAR), we systematically altered the substituents in the 2-, 4-, 5-, 6-, and 7-position of the pteridine nucleus. Varying the substitution pattern in the 2-, 5-, and 7-position resulted in no significant inhibitory effect on enzyme activity. In contrast, bulky substituents in the B-position, such as phenyl, markedly increased the inhibitory potency of the reduced 4-amino-5,6,7,8-tetrahydropteridines, possibly as a consequence of hydrophobic interactions within NOS-I. However, this was not the case for the aromatic 4-amino pteridines. Interestingly, chemical modification of the 4-amino substituent by dialkyl/diaralkylation together with 6-arylation of the aromatic 2,4-diamino pteridine resulted in potent and efficacious inhibitors of NOS-I, suggesting possible hydrophilic and hydrophobic interactions within NOS-I. This SAR agrees with (a) the recently published crystal structure of the oxygenase domain of the inducible NOS isoform (NOS-II) and (b) the comparative molecular field analysis of selected NOS-I inhibitors, which resulted in a 3D-QSAR model of the pterin binding site interactions. Further optimization should be possible when the full length structure of NOS-I becomes available.

  DOI：

  10.1021/jm981129a

文献信息

• NOVEL METHOTREXATE DERIVATIVE
  申请人：Chugai Seiyaku Kabushiki Kaisha

  公开号：EP0543997A1

  公开（公告）日：1993-06-02

  A compound represented by general formula (A), which is useful as a medicine because it has potent antirheumatic, psoriasis curing and anticancer actions and a reduced toxicity, wherein R¹ represents CH₂, CH₂CH₂, CH₂O, CH₂S or CH₂SO; R² represents hydrogen, C₁ to C₄ lower alkyl or benzyl; R³ represents COOR⁴, NHCOR⁵, CONR⁶R⁷, PO₃H₂ or SO₃H; and n represents an integer of 1 to 4.

  一种由通式(A)表示的化合物，因其具有强效抗风湿、治疗牛皮癣和抗癌作用且毒性较低而可用作药物，其中 R¹ 代表 CH₂、CH₂CH₂、CH₂O、CH₂S 或 CH₂SO；R² 代表氢、C₁ 至 C₄ 低级烷基或苄；R³ 代表 COOR⁴、NHCOR⁵、CONR⁶R⁷、PO₃H₂ 或 SO₃H；以及 n 代表 1 至 4 的整数。
• DERIVATIVES OF METHOTREXATE WITH ANTIRHEUMATIC ACTIVITY
  申请人：Chugai Seiyaku Kabushiki Kaisha

  公开号：EP0543997B1

  公开（公告）日：1999-12-08
• US5354753A
  申请人：——

  公开号：US5354753A

  公开（公告）日：1994-10-11
• Inhibition of Neuronal Nitric Oxide Synthase by 4-Amino Pteridine Derivatives:  Structure−Activity Relationship of Antagonists of (6<i>R</i>)-5,6,7,8-Tetrahydrobiopterin Cofactor
  作者：Lothar G. Fröhlich、Peter Kotsonis、Hermann Traub、Shahriyar Taghavi-Moghadam、Najim Al-Masoudi、Heinrich Hofmann、Hartmut Strobel、Hans Matter、Wolfgang Pfleiderer、Harald H. H. W. Schmidt

  DOI：10.1021/jm981129a

  日期：1999.10.1

  The family of nitric oxide synthases (NOS) catalyzes the conversion of L-arginine to L-citrulline and nitric oxide (NO), an important cellular messenger molecule which has been implicated in the pathophysiology of septic shock and inflammatory and neurodegenerative disease states. NOS can be maximally activated by the ubiquitous cofactor, (6R)-5,6,7,8-tetrahydrobiopterin (H(4)Bip), and antagonists of H(4)Bip may be of therapeutic importance to inhibit pathologically high NO formation. The 4-amino substituted analogue of H(4)Bip was reported to be a potent NOS inhibit-or. Therefore, we developed a series of novel 4-amino pteridine derivatives, antipterins, to pharmacologically target the neuronal isoform of nitric oxide synthase (NOS-I). To functionally characterize the pterin/anti-pterin interaction and establish a structure-activity relationship (SAR), we systematically altered the substituents in the 2-, 4-, 5-, 6-, and 7-position of the pteridine nucleus. Varying the substitution pattern in the 2-, 5-, and 7-position resulted in no significant inhibitory effect on enzyme activity. In contrast, bulky substituents in the B-position, such as phenyl, markedly increased the inhibitory potency of the reduced 4-amino-5,6,7,8-tetrahydropteridines, possibly as a consequence of hydrophobic interactions within NOS-I. However, this was not the case for the aromatic 4-amino pteridines. Interestingly, chemical modification of the 4-amino substituent by dialkyl/diaralkylation together with 6-arylation of the aromatic 2,4-diamino pteridine resulted in potent and efficacious inhibitors of NOS-I, suggesting possible hydrophilic and hydrophobic interactions within NOS-I. This SAR agrees with (a) the recently published crystal structure of the oxygenase domain of the inducible NOS isoform (NOS-II) and (b) the comparative molecular field analysis of selected NOS-I inhibitors, which resulted in a 3D-QSAR model of the pterin binding site interactions. Further optimization should be possible when the full length structure of NOS-I becomes available.