Identification of a Novel 2,8-Diazaspiro[4.5]decan-1-one Derivative as a Potent and Selective Dual TYK2/JAK1 Inhibitor for the Treatment of Inflammatory Bowel Disease

In
this study, we described a series of 2,8-diazaspiro[4.5]­decan-1-one
derivatives as selective TYK2/JAK1 inhibitors. Systematic exploration
of the structure–activity relationship through the introduction
of spirocyclic scaffolds based on the reported selective TYK2 inhibitor 14l led to the discovery of the superior derivative compound 48. Compound 48 showed excellent potency on TYK2/JAK1
kinases with IC50 values of 6 and 37 nM, respectively,
and exhibited more than 23-fold selectivity for JAK2. Compound 48 also demonstrated excellent metabolic stability and more
potent anti-inflammatory efficacy than tofacitinib in acute ulcerative
colitis models. Moreover, the excellent anti-inflammatory effect of
compound 48 was mediated by regulating the expression
of related TYK2/JAK1-regulated genes, as well as the formation of
Th1, Th2, and Th17 cells. Taken together, these findings suggest that
compound 48 is a selective dual TYK2/JAK inhibitor, deserving
to be developed as a clinical candidate.

本研究报道了一系列2,8-二氮杂螺[4.5]癸烷-1-酮衍生物，该类化合物可作为选择性TYK2/JAK1抑制剂。基于已报道的选择性TYK2抑制剂14l，通过引入螺环骨架系统开展构效关系研究，最终发现了活性更优的衍生物化合物48。化合物48对TYK2与JAK1激酶展现出优异的抑制活性，其半数抑制浓度（IC50）分别为6 nM与37 nM，且对JAK2的选择性超过23倍。此外，化合物48具备优异的代谢稳定性，且在急性溃疡性结肠炎模型中展现出优于托法替布的抗炎活性。进一步研究表明，化合物48的优异抗炎作用可通过调控受TYK2/JAK1通路调控的相关基因表达，以及调节Th1、Th2与Th17细胞的分化与生成来实现。综上，本研究结果显示化合物48是一款选择性双重TYK2/JAK抑制剂，具备开发为临床候选药物的潜力。