1-(cyclopropylmethyl)-2,2-dimethyl-7-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2,3-dihydroquinazolin-4(1H)-one

• 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: 1-(cyclopropylmethyl)-2,2-dimethyl-7-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2,3-dihydroquinazolin-4(1H)-one
• 英文别名: 1-(cyclopropylmethyl)-2,2-dimethyl-7-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)-3H-quinazolin-4-one
• 化学式: C₂₀H₂₁N₅O₂
• 分子量: 363.419
• InChiKey: WWMNGOSHFBCVEU-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  77.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2-氟-4-溴苯腈 在 吡啶 、 tris-(dibenzylideneacetone)dipalladium(0) 、 溶剂黄146 、 sodium t-butanolate 、 2-二环己基磷-2',6'-二异丙氧基-1,1'-联苯 作用下， 以 丙酮 、 叔丁醇 为溶剂， 反应 3.0h， 生成 1-(cyclopropylmethyl)-2,2-dimethyl-7-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)-2,3-dihydroquinazolin-4(1H)-one
  参考文献：
  名称：

  Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors

  摘要：

  A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-theta (PKC theta) inhibitor. Using the docking model of compound 1 bound to PKC theta as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic sub-stituent boosted PKC theta inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKC theta confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2016.04.008

文献信息

• Discovery and optimization of 1,7-disubstituted-2,2-dimethyl-2,3-dihydroquinazolin-4(1H)-ones as potent and selective PKCθ inhibitors
  作者：Taisuke Katoh、Takafumi Takai、Takafumi Yukawa、Tetsuya Tsukamoto、Etsurou Watanabe、Hideyuki Mototani、Takeo Arita、Hiroki Hayashi、Hideyuki Nakagawa、Michael G. Klein、Hua Zou、Bi-Ching Sang、Gyorgy Snell、Yoshihisa Nakada

  DOI：10.1016/j.bmc.2016.04.008

  日期：2016.6

  A high-throughput screening campaign helped us to identify an initial lead compound (1) as a protein kinase C-theta (PKC theta) inhibitor. Using the docking model of compound 1 bound to PKC theta as a model, structure-based drug design was employed and two regions were identified that could be explored for further optimization, i.e., (a) a hydrophilic region around Thr442, unique to PKC family, in the inner part of the hinge region, and (b) a lipophilic region at the forefront of the ethyl moiety. Optimization of the hinge binder led us to find 1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one as a potent and selective hinge binder, which resulted in the discovery of compound 5. Filling the lipophilic region with a suitable lipophilic sub-stituent boosted PKC theta inhibitory activity and led to the identification of compound 10. The co-crystal structure of compound 10 bound to PKC theta confirmed that both the hydrophilic and lipophilic regions were fully utilized. Further optimization of compound 10 led us to compound 14, which demonstrated an improved pharmacokinetic profile and inhibition of IL-2 production in a mouse. (C) 2016 Elsevier Ltd. All rights reserved.