871254-61-4Relevant articles and documents
Novel 1H-pyrazolo[3,4-d]pyrimidin-6-amino derivatives as potent selective Janus kinase 3 (JAK3) inhibitors. Evaluation of their improved effect for the treatment of rheumatoid arthritis
Chen, Cheng-Juan,Shu, Lei,Wang, Zhi-Jian,Yin, Yuan,Yu, Ru-Nan,Zhang, Da-Yong,Zhang, Tian-Tai
, (2020/03/17)
Selective JAK3 inhibitors have been shown to have a potential benefit in the treatment of autoimmune disorders. Here we report the identification of a series of pyrazolopyrimidine derivatives as potent JAK3 inhibitors that exploit a unique cysteine (Cys909) residue in JAK3. Most of these compounds (13k, 13n and 13 t), displayed stronger anti-JAK3 kinase activity and selectivity than tofacitinib. Furthermore, the most active inhibitor 13t (IC50 = 0.1 nM), also exhibited favourable selectivity for JAK3 in a panel of 9 kinases which contain the same cysteine. In a series of cytokinestimulated cellular analysis, compound 13 t, could potently block the JAK3-STAT signaling pathway. Further biological studies, including cellular antiproliferative activity assays and a rat adjuvant-induced arthritis model for in vivo evaluation, also indicated its efficacy and low toxicity in the treatment of rheumatoid arthritis. The results of these experimental explorations suggested that 13t is a promising lead compound for the development of selective JAK3 inhibitor with therapeutic potential in rheumatoid arthritis.
Discovery of novel dual extracellular regulated protein kinases (Erk) and phosphoinositide 3-kinase (pi3k) inhibitors as a promising strategy for cancer therapy
Guan, Zhe,Huang, Lei,Ju, Qiurong,Li, Yin,Sun, Jinjin,Wang, Shuping,Wu, Shiqi,Xu, Yungen,Zhang, Lingzhi,Zhu, Qihua
, (2021/06/14)
Concomitant inhibition of MAPK and PI3K signaling pathways has been recognized as a promising strategy for cancer therapy, which effectively overcomes the drug resistance of MAPK signaling pathway-related inhibitors. Herein, we report the scaffold-hopping generation of a series of 1H-pyrazolo[3,4-d]pyrimidine dual ERK/PI3K inhibitors. Compound 32d was the most promising candidate, with potent inhibitory activities against both ERK2 and PI3Kα which displays superior anti-proliferative profiles against HCT116 and HEC1B cancer cells. Meanwhile, compound 32d possessed acceptable pharmacokinetic profiles and showed more efficacious anti-tumor activity than GDDC-0980 and the corresponding drug combination (BVD-523 + GDDC-0980) in HCT-116 xenograft model, with a tumor growth inhibitory rate of 51% without causing observable toxic effects. All the results indicated that 32d was a highly effective anticancer compound and provided a promising basis for further optimization towards dual ERK/PI3K inhibitors.
Preparation method of pharmaceutical intermediate 2,4-dichloro-5-pyrimidine formaldehyde
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Paragraph 0014; 0015, (2018/09/26)
The invention discloses a preparation method of a pharmaceutical intermediate 2,4-dichloro-5-pyrimidine formaldehyde, and belongs to the technical field of pharmaceutical synthesis. According to the key point of the technical scheme, the preparation method comprises the steps: uracil is used as a starting material, Vilsmeier-Haack reaction is carried out at low temperature and aldehyde groups arenot subjected to chlorination reaction under protection of a protective agent aluminum trichloride or boric acid, then heating is carried out, and chlorination reaction is carried out with phosphorusoxychloride to generate the target product pharmaceutical intermediate 2,4-dichloro-5-pyrimidine formaldehyde. The preparation method has the advantages of mild reaction conditions, high yield and good product purity, and is a synthetic method with industrial production value.
