Discovery ofSelective 17β-HSD13 InhibitorsContaining a Phenol Isostere

Hydroxysteroid 17-β-dehydrogenase 13 is a liver-specific, lipid-droplet enzyme genetically linked to reduced risk of metabolic-associated steatotic liver disease (MASLD), making it a compelling therapeutic target for metabolic dysfunction–associated steatohepatitis. Herein, we describe optimization of a series of small-molecule 17β-HSD13 inhibitors originating from a carboxylic acid hit identified in a high-throughput screen. Advancement to a phenol-based series of interest showed potent biochemical activity but poor pharmacokinetic profiles. Discovery efforts focused on replacement of the metabolically liable phenol pharmacophore and led to identification of a pyrimidinone isostere demonstrating lower lipophilicity, no glucuronidation, significantly improved metabolic stability, and extended rodent plasma mean residence times. Extensive optimization of the additional vectors led to inhibitors with nanomolar cellular activity while preserving selectivity, solubility, and in vivo stability (exemplified by lead inhibitor 25). Our findings establish the pyrimidinone motif as a general phenol isostere for improving pharmacokinetic properties in 17β-HSD13 inhibitors and beyond.