Discovery of Highly Potent, Selective, and Liver-Targeting HSD17B13 Inhibitor with Robust In Vivo Anti-MASH Activity

Metabolic dysfunction-associated steatohepatitis (MASH) is one of the most common chronic liver diseases, driven by diverse genetic and environmental factors. Extensive human genetics' studies have indicated that HSD17B13 is emerging as a promising therapeutic target for MASH. However, no <i>in vivo</i> efficacy of a HSD17B13 inhibitor has been reported. Herein, multiparameter optimization studies led to the discovery of a highly potent and selective HSD17B13 inhibitor <b>32</b> (IC₅₀ = 2.5 nM), which demonstrated significantly better liver microsomal stability and pharmacokinetic profile compared to BI-3231. Moreover, the unique liver-targeting profile of compound <b>32</b> provided greater potential for the treatment of MASH. In multiple mouse models, compound <b>32</b> exhibited better anti-MASH effects compared to BI-3231. Further mechanistic studies indicated that compound <b>32</b> regulated hepatic lipids by inhibiting the SREBP-1c/FAS pathway. Based on these positive results, HSD17B13 inhibitor <b>32</b> is worthy of further evaluation as the first pharmacological tool with robust <i>in vivo</i> anti-MASH activity.