2-(4-((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]-pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide | 1381878-12-1

• 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-(4-((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]-pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide
• 英文别名: 2-[4-[[2-(1H-indol-4-yl)-4-morpholin-4-ylthieno[3,2-d]pyrimidin-6-yl]methyl]piperazin-1-yl]-2-methylpropanamide
• CAS: 1381878-12-1
• 化学式: C₂₇H₃₃N₇O₂S
• 分子量: 519.671
• InChiKey: IVYRXHYGYPSVTM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  37
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  132
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  tert-butyl 4-(1-amino-2-methyl-1-oxopropan-2-yl)piperazine-1-carboxylate 在 盐酸 、 四(三苯基膦)钯 、 caesium carbonate 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 水 为溶剂， 反应 48.33h， 生成 2-(4-((2-(1H-indol-4-yl)-4-morpholinothieno[3,2-d]-pyrimidin-6-yl)methyl)piperazin-1-yl)-2-methylpropanamide
  参考文献：
  名称：

  Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition

  摘要：

  PI3K delta is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(alpha, beta, delta) and IB (gamma), which catalyze the phosphorylation of PIP2 to PIP3. PI3K delta is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3K delta inhibitors and describe a structural hypothesis for isoform (alpha, beta, gamma) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.

  DOI：

  10.1021/jm3003747

文献信息

• Discovery of Novel PI3-Kinase δ Specific Inhibitors for the Treatment of Rheumatoid Arthritis: Taming CYP3A4 Time-Dependent Inhibition
  作者：Brian S. Safina、Stewart Baker、Matt Baumgardner、Paul M. Blaney、Bryan K. Chan、Yung-Hsiang Chen、Matthew W. Cartwright、Georgette Castanedo、Christine Chabot、Arnaud J. Cheguillaume、Paul Goldsmith、David M. Goldstein、Bindu Goyal、Timothy Hancox、Raj K. Handa、Pravin S Iyer、Jasmit Kaur、Rama Kondru、Jane R. Kenny、Sussie L. Krintel、Jun Li、John Lesnick、Matthew C. Lucas、Cristina Lewis、Sophie Mukadam、Jeremy Murray、Alan J. Nadin、Jim Nonomiya、Fernando Padilla、Wylie S. Palmer、Jodie Pang、Neil Pegg、Steve Price、Karin Reif、Laurent Salphati、Pascal A. Savy、Eileen M. Seward、Stephen Shuttleworth、Sukhjit Sohal、Zachary K. Sweeney、Suzanne Tay、Parcharee Tivitmahaisoon、Bohdan Waszkowycz、Binqing Wei、Qin Yue、Chenghong Zhang、Daniel P. Sutherlin

  DOI：10.1021/jm3003747

  日期：2012.6.28

  PI3K delta is a lipid kinase and a member of a larger family of enzymes, PI3K class IA(alpha, beta, delta) and IB (gamma), which catalyze the phosphorylation of PIP2 to PIP3. PI3K delta is mainly expressed in leukocytes, where it plays a critical, nonredundant role in B cell receptor mediated signaling and provides an attractive opportunity to treat diseases where B cell activity is essential, e.g., rheumatoid arthritis. We report the discovery of novel, potent, and selective PI3K delta inhibitors and describe a structural hypothesis for isoform (alpha, beta, gamma) selectivity gained from interactions in the affinity pocket. The critical component of our initial pharmacophore for isoform selectivity was strongly associated with CYP3A4 time-dependent inhibition (TDI). We describe a variety of strategies and methods for monitoring and attenuating TDI. Ultimately, a structure-based design approach was employed to identify a suitable structural replacement for further optimization.