Discovery of Selective 17β-HSD13 Inhibitors Containing a Phenol Isostere

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Hepatology

Background:

• Hydroxysteroid 17-β-dehydrogenase 13 (17β-HSD13) is a liver enzyme linked to reduced risk of metabolic-associated steatotic liver disease (MASLD).
• 17β-HSD13 is a potential therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH).

Purpose of the Study:

• To optimize small-molecule inhibitors of 17β-HSD13.
• To improve pharmacokinetic properties of 17β-HSD13 inhibitors by replacing a metabolically unstable phenol group.

Main Methods:

• High-throughput screening identified initial carboxylic acid inhibitors.
• Medicinal chemistry efforts focused on structure-activity and structure-property relationships.
• Optimization involved exploring isosteric replacements for the phenol pharmacophore, leading to pyrimidinone analogs.

Main Results:

• A pyrimidinone isostere demonstrated reduced lipophilicity, no glucuronidation, and enhanced metabolic stability.
• Optimized inhibitors achieved nanomolar cellular activity.
• Lead inhibitor 25 exhibited preserved selectivity, solubility, and in vivo stability with extended rodent plasma half-life.

Conclusions:

• The pyrimidinone motif serves as a viable phenol isostere for enhancing pharmacokinetic profiles.
• This strategy is applicable for developing 17β-HSD13 inhibitors and other drug candidates.
• The optimized inhibitors represent promising leads for treating MASLD and MASH.