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

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-3carboxamide 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.

Automated summary

In this study, we reported the design, synthesis, and structure-activity relationships (SARs) of N-(methyl-d3) pyridazine-3carboxamide derivatives as TYK2 inhibitors. Compound 24 exhibited acceptable inhibition activity against STAT3 phosphorylation and demonstrated satisfactory selectivities toward other members of JAK family. Moreover, compound 24 showed good stability profile in liver microsomal assay and reasonable pharmacokinetics (PK) exposures. In anti-CD40-induced colitis models, compound 24 was orally highly effective with no significant hERG and CYP isozymes inhibition. These findings highlight the potential of compound 24 as a candidate for the development of anti-autoimmunity diseases agents.