治疗类风湿关节炎的选择性抑制剂的开发：（R）-3-（3-（甲基（7H-吡咯并[2,3-d]嘧啶-4-基）氨基）吡咯烷-1-基）-3-氧代丙腈作为一种 JAK1 选择性抑制剂。
Development of selective inhibitors for the treatment of rheumatoid arthritis: (R)-3-(3-(Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor.
机构信息
Department of Chemistry, College of Natural Sciences, Seoul National University, Seoul 08876, South Korea.
Yang Ji Chemical Co., Ltd., Gyeonggi Bio-Center, Suwon, Gyeonggi-do 16229, South Korea.
出版信息
Bioorg Med Chem. 2018 May 1;26(8):1495-1510. doi: 10.1016/j.bmc.2018.01.021. Epub 2018 Feb 3.
A series of 3(R)-aminopyrrolidine derivatives were designed and synthesized for JAK1-selective inhibitors through the modification of tofacitinib's core structure, (3R,4R)-3-amino-4-methylpiperidine. From the new core structures, we selected (R)-N-methyl-N-(pyrrolidin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine as a scaffold for further SAR studies. From biochemical enzyme assays and liver microsomal stability tests, (R)-3-(3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)pyrrolidin-1-yl)-3-oxopropanenitrile (6) was chosen for further in vivo test through oral administration. Compound 6 showed improved selectivity for JAK1 compared to that of tofacitinib (IC 11, 2.4 × 10, 2.8 × 10, and 1.1 × 10 nM for JAK1, JAK2, JAK3, and TYK2, respectively). In CIA and AIA model tests, compound 6 exhibited similar efficacy to tofacitinib citrate.
一系列 3(R)-氨基吡咯烷衍生物被设计和合成，作为 JAK1 选择性抑制剂，通过对托法替尼核心结构（（3R,4R）-3-氨基-4-甲基哌啶）的修饰。从新的核心结构中，我们选择（R）-N-甲基-N-（吡咯烷-3-基）-7H-吡咯并[2,3-d]嘧啶-4-胺作为进一步 SAR 研究的支架。通过生化酶测定和肝微粒体稳定性测试，（R）-3-(3-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)吡咯烷-1-基)-3-氧代丙腈（6）被选为进一步通过口服给药进行体内测试的化合物。与托法替尼相比，化合物 6对 JAK1 的选择性提高（IC 11，分别为 2.4×10、2.8×10 和 1.1×10 nM 用于 JAK1、JAK2、JAK3 和 TYK2）。在 CIA 和 AIA 模型测试中，化合物 6表现出与柠檬酸托法替尼相似的疗效。
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