Discovery of a Novel Ketohexokinase Inhibitor with Improved Drug Distribution in Target Tissue for the Treatment of Fructose Metabolic Disease

Excessive fructose absorption and its subsequent metabolisms are implicated in nonalcoholic fatty liver disease, obesity, and insulin resistance in humans. Ketohexokinase (KHK) is a primary enzyme involved in fructose metabolism via the conversion of fructose to fructose-1-phosphate. KHK inhibition might be a potential approach for the treatment of metabolic disorders. Herein, a series of novel KHK inhibitors were designed, synthesized, and evaluated. Among them, compound 14 exhibited more potent activity than PF-06835919 based on the rat KHK inhibition assay in vivo, and higher drug distribution concentration in the liver. Its good absorption, distribution, metabolism, and excretion and pharmacokinetic properties make it a promising clinical candidate.