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Design, synthesis, and pharmacological evaluation of quinazoline derivatives as novel and potent pan-JAK inhibitors. 2023

Jinbao Xiang, and Yuji Wang, and Wanhe Wang, and Jianxin Yu, and Lianyou Zheng, and Yuan Hong, and Lingling Shi, and Chunling Zhang, and Na Chen, and Jia Xu, and Xuelian Gong, and Zhuoqi Zhang, and Hongming Cui, and Qian Zhou, and Dapeng Zhang, and Yanjun Liu, and Ying Ke, and Jingkang Shen, and Guangxin Xia, and Xu Bai
The Center for Combinatorial Chemistry and Drug Discovery of Jilin University, The School of Pharmaceutical Sciences, Jilin University, Changchun, Jilin 130021, PR China.

Janus kinases (JAKs) play a critical role in modulating the function and expression of inflammatory cytokines related to rheumatoid arthritis (RA). Herein, we report the design, synthesis, and structure-activity relationships (SARs) of a series of novel quinazoline derivatives as JAK inhibitors. Among these inhibitors, compound 11n showed high potency against JAKs (JAK1/JAK2/JAK3/TYK2, IC50 = 0.40, 0.83, 2.10, 1.95 nM), desirable metabolic characters, and excellent pharmacokinetic properties. In collagen-induced arthritis (CIA) models, compound 11n exhibited significant reduction in joint swelling with good safety, which could be served as a potential therapeutic candidate for the treatment of inflammatory diseases.

UI MeSH Term Description Entries
D011799 Quinazolines A group of aromatic heterocyclic compounds that contain a bicyclic structure with two fused six-membered aromatic rings, a benzene ring and a pyrimidine ring. Quinazoline
D006801 Humans Members of the species Homo sapiens. Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000075242 Janus Kinase Inhibitors Agents that inhibit JANUS KINASES. JAK Inhibitor,Janus Kinase Inhibitor,JAK Inhibitors,Inhibitor, JAK,Inhibitor, Janus Kinase,Inhibitors, JAK,Inhibitors, Janus Kinase,Kinase Inhibitor, Janus,Kinase Inhibitors, Janus
D001172 Arthritis, Rheumatoid A chronic systemic disease, primarily of the joints, marked by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. Etiology is unknown, but autoimmune mechanisms have been implicated. Rheumatoid Arthritis
D013329 Structure-Activity Relationship The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups. Relationship, Structure-Activity,Relationships, Structure-Activity,Structure Activity Relationship,Structure-Activity Relationships
D047428 Protein Kinase Inhibitors Agents that inhibit PROTEIN KINASES. Protein Kinase Inhibitor,Inhibitor, Protein Kinase,Inhibitors, Protein Kinase,Kinase Inhibitor, Protein,Kinase Inhibitors, Protein
D053612 Janus Kinases A family of intracellular tyrosine kinases that participate in the signaling cascade of cytokines by associating with specific CYTOKINE RECEPTORS. They act upon STAT TRANSCRIPTION FACTORS in signaling pathway referred to as the JAK/STAT pathway. The name Janus kinase refers to the fact the proteins have two phosphate-transferring domains. Janus Kinase,JAK Kinases,Kinase, Janus,Kinases, JAK,Kinases, Janus

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