Discovery of the First-In-Class HSD17B13/PPAR Multitarget Modulators for the Treatment of Metabolic Dysfunction-Associated Steatohepatitis

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex disease driven by multiple metabolic and inflammatory pathways. HSD17B13 is a potential therapeutic target for MASH, and PPAR regulates multiple pathological mechanisms related to MASH. Based on their important roles, we hypothesize that the HSD17B13/PPAR multitarget modulator may have a better effect in targeting multiple pathological mechanisms of MASH. In this study, a structure-based hybrid strategy was performed by integrating the key pharmacophores of a PPAR agonist and an HSD17B13 inhibitor to design HSD17B13/PPAR multitarget modulators. After multiparametric structural optimization, the HSD17B13/PPAR multitarget modulator <b>17</b> (HSD17B13 IC₅₀ = 0.91 μM, PPARα/δ/γ EC₅₀ = 1.55/0.12/0.01 μM) has been identified, which exhibited high liver-targeting distribution and suitable pharmacokinetic properties. In addition, compound <b>17</b> revealed better anti-MASH effects than BI-3231 in ameliorating MASH-associated steatosis, inflammation, and fibrosis. Based on these results, compound <b>17</b> is worthy of further evaluation as a first-in-class HSD17B13/PPAR modulator with robust anti-MASH activity.