(6aS,7S,10aR)-2-anilino-7-methyl-8-oxo-10a-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: (6aS,7S,10aR)-2-anilino-7-methyl-8-oxo-10a-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile
• 英文别名: IDH1 Inhibitor 2；(6aS,7S,10aR)-2-anilino-7-methyl-8-oxo-10a-phenyl-5,6,6a,7-tetrahydrobenzo[h]quinazoline-9-carbonitrile
• 化学式: C₂₆H₂₂N₄O
• 分子量: 406.487
• InChiKey: BCWIIGSNDGENBB-VAQYAFAPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  78.7
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  2-苯基环己烷-1,3-二酮 在 吡啶 、 sodium tetrahydroborate 、 重铬酸吡啶 、 1,3-二溴-5,5-二甲基海因 、 乙醇 、 palladium on carbon 、 potassium tert-butylate 、 氢气 、 magnesium sulfate 、 对甲苯磺酸 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 乙腈 为溶剂， -5.0~90.0 ℃ 、689.49 kPa 条件下， 反应 111.0h， 生成 (6aS,7S,10aR)-2-anilino-7-methyl-8-oxo-10a-phenyl-5,6,6a,7,8,10a-hexahydrobenzo[h]quinazoline-9-carbonitrile
  参考文献：
  名称：

  Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315

  摘要：

  IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive alpha,beta-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine underutilized strategy for reversible covalent small molecule design. residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.

  DOI：

  10.1021/acs.jmedchem.8b00305

文献信息

• ARYL AND ARYLALKYL SUBSTITUTED PYRAZOLYL AND PYRIMIDINYL TRICYCLIC ENONES AS ANTIOXIDANT INFLAMMATION MODULATORS
  申请人：AbbVie Inc.

  公开号：US20150225397A1

  公开（公告）日：2015-08-13

  The present application relates to: (a) compounds of Formula (I): and salts thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , m, n, X and Y are as defined in the specification; (b) compositions comprising such compounds and salts; and (c) methods of use of such compounds, salts, and compositions, particularly use for the treatment and prevention of diseases such as those associated with oxidative stress and inflammation.

  本申请涉及：(a) 公式(I)的化合物及其盐，其中R1、R2、R3、R4、R5、R6、m、n、X和Y如规范中定义；(b) 包含这些化合物和盐的组合物；以及(c) 这些化合物、盐和组合物的使用方法，特别是用于治疗和预防与氧化应激和炎症相关的疾病。
• US9464082B2
  申请人：——

  公开号：US9464082B2

  公开（公告）日：2016-10-11
• Novel Modes of Inhibition of Wild-Type Isocitrate Dehydrogenase 1 (IDH1): Direct Covalent Modification of His315
  作者：Clarissa G. Jakob、Anup K. Upadhyay、Pamela L. Donner、Emily Nicholl、Sadiya N. Addo、Wei Qiu、Christopher Ling、Sujatha M. Gopalakrishnan、Maricel Torrent、Steven P. Cepa、Jason Shanley、Alexander R. Shoemaker、Chaohong C. Sun、Anil Vasudevan、Kevin R. Woller、J. Brad Shotwell、Bailin Shaw、Zhiguo Bian、Jessica E. Hutti

  DOI：10.1021/acs.jmedchem.8b00305

  日期：2018.8.9

  IDH1 plays a critical role in a number of metabolic processes and serves as a key source of cytosolic NADPH under conditions of cellular stress. However, few inhibitors of wild-type IDH1 have been reported. Here we present the discovery and biochemical characterization of two novel inhibitors of wild-type IDH1. In addition, we present the first ligand-bound crystallographic characterization of these novel small molecule IDH1 binding pockets. Importantly, the NADPH competitive alpha,beta-unsaturated enone 1 makes a unique covalent linkage through active site H315. As few small molecules have been shown to covalently react with histidine underutilized strategy for reversible covalent small molecule design. residues, these data support the potential utility of an underutilized strategy for reversible covalent small molecule design.