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Design, synthesis and biological evaluation of novel N-(methyl-d3) pyridazine-3-carboxamide derivatives as TYK2 inhibitors. 2023

Fei Liu, and Bin Wang, and Yanlong Liu, and Wei Shi, and Zhongyuan Hu, and Xiayun Chang, and Xujing Tang, and Ying Zhang, and Hongjiang Xu, and Ying He
School of Chemistry and Chemical Engineering, Nanjing University of Science and Technology, Nanjing 210094, China; R&D Institute, Chia Tai Tianqing Pharmaceutical Group Co., Ltd, 1099 Fuying Road, Jiangning District, Nanjing, Jiangsu Province, China.

As a mediator of pro-inflammatory cytokines, TYK2 is an attractive target to treat autoimmunity diseases. Herein, we reported the design, synthesis, and structure-activity relationships (SARs) of N-(methyl-d3) pyridazine-3-carboxamide derivatives as TYK2 inhibitors. Among them, compound 24 exhibited acceptable inhibition activity against STAT3 phosphorylation. Furthermore, 24 showed satisfactory selectivities toward other members of JAK family and performed a good stability profile in liver microsomal assay. Pharmacokinetics (PK) study indicated that compound 24 has reasonable PK exposures. In anti-CD40-induced colitis models, compound 24 was orally highly effective with no significant hERG and CYP isozymes inhibition. These results indicated that compound 24 was worthy of further investigation for the development of anti-autoimmunity diseases agents.

UI MeSH Term Description Entries
D010766 Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Phosphorylations
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
D053634 TYK2 Kinase A Janus kinase subtype that is involved in signaling from a broad variety of CYTOKINE RECEPTORS. The TYK2 kinase is considered the founding member of the janus kinase family and was initially discovered as a signaling partner for the INTERFERON ALPHA-BETA RECEPTOR. The kinase has since been shown to signal from several INTERLEUKIN RECEPTORS. Non-Receptor Tyrosine-Protein Kinase TYK2,Tyrosine Kinase 2,Kinase, TYK2,Non Receptor Tyrosine Protein Kinase TYK2

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