Atopic dermatitis is a chronic inflammatory skin disease due to aberrant immunological reactions as one of the leading etiologies. Topical steroids and tacrolimus ointment, which are standard therapeutic agents, have side effects such as skin thinning and irritation. Therefore, there is an urgent medical need to develop new safety therapeutic agents. Janus kinases (JAK1, JAK2, JAK3, Tyk2) are intracellular tyrosine kinases, play critical role in intracellular signal transduction, and have drawn

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... significant attention as attractive therapeutic target for autoimmune inflammatory diseases. We conducted to develop a novel JAK3 inhibitor for new immunomodulator. Regarding SAR exploration, to be obtain high kinase selectively, we considered and investigated three-dimensionality in the compound. As the result, we succeeded in discovery of delgocitinib bearing spiro scaffold, which showed high JAK3 inhibitory activity and high kinase selectivity. Delgocitinib ointment received manufacturing and marketing approval in Japan as the world's first topical JAK inhibitor for the treatment of atopic dermatitis.