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

Abstract

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 <b>14l</b> led to the discovery of the superior derivative compound <b>48</b>. Compound <b>48</b> 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 <b>48</b> 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 <b>48</b> 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 <b>48</b> is a selective dual TYK2/JAK inhibitor, deserving to be developed as a clinical candidate.