(S)-4-(1-cyclopropyl-3-hydroxypropan-2-ylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: (S)-4-(1-cyclopropyl-3-hydroxypropan-2-ylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide
• 英文别名: 4-[[(2S)-1-cyclopropyl-3-hydroxypropan-2-yl]amino]-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide
• 化学式: C₂₀H₂₃N₅O₃
• 分子量: 381.434
• InChiKey: ACLSCELQVISBCN-HNNXBMFYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  4-溴-1H-吡咯-2-羧酸甲酯 在 Oxone 、 potassium phosphate 、 硫酸 、 palladium diacetate 、 sodium hydride 、 potassium carbonate 、 2-二环己基磷-2,4,6-三异丙基联苯 、 三氯氧磷 作用下， 以 1,4-二氧六环 、 N-甲基吡咯烷酮 、 水 、 N,N-二甲基甲酰胺 、 异丙醇 、 丙酮 、 mineral oil 为溶剂， 反应 42.75h， 生成 (S)-4-(1-cyclopropyl-3-hydroxypropan-2-ylamino)-6-(6-methoxypyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide
  参考文献：
  名称：

  Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis

  摘要：

  The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.

  DOI：

  10.1021/acsmedchemlett.8b00508

文献信息

• Discovery of a JAK1/3 Inhibitor and Use of a Prodrug To Demonstrate Efficacy in a Model of Rheumatoid Arthritis
  作者：Steven H. Spergel、Michael E. Mertzman、James Kempson、Junqing Guo、Sylwia Stachura、Lauren Haque、Jonathan S. Lippy、Rosemary F. Zhang、Michael Galella、Sidney Pitt、Guoxiang Shen、Aberra Fura、Kathleen Gillooly、Kim W. McIntyre、Vicky Tang、John Tokarski、John S. Sack、Javed Khan、Percy H. Carter、Joel C. Barrish、Steven G. Nadler、Luisa M. Salter-Cid、Gary L. Schieven、Stephen T. Wrobleski、William J. Pitts

  DOI：10.1021/acsmedchemlett.8b00508

  日期：2019.3.14

  The four members of the Janus family of nonreceptor tyrosine kinases play a significant role in immune function. The JAK family kinase inhibitor, tofacitinib 1, has been approved in the United States for use in rheumatoid arthritis (RA) patients. A number of JAK inhibitors with a variety of JAK family selectivity profiles are currently in clinical trials. Our goal was to identify inhibitors that were functionally selective for JAK1 and JAK3. Compound 22 was prepared with the desired functional selectivity profile, but it suffered from poor absorption related to physical properties. Use of the phosphate prodrug 32 enabled progression to a murine collagen induced arthritis (CIA) model. The demonstration of a robust efficacy in the CIA model suggests that use of phosphate prodrugs may resolve issues with progressing this chemotype for the treatment of autoimmune diseases such as RA.