Discovery of Fragment-Derived Small Molecules for in Vivo Inhibition of Ketohexokinase (KHK)

Increased
fructose consumption and its subsequent metabolism have
been implicated in hepatic steatosis, dyslipidemia, obesity, and insulin
resistance in humans. Since ketohexokinase (KHK) is the principal
enzyme responsible for fructose metabolism, identification of a selective
KHK inhibitor may help to further elucidate the effect of KHK inhibition
on these metabolic disorders. Until now, studies on KHK inhibition
with small molecules have been limited due to the lack of viable in
vivo pharmacological tools. Herein we report the discovery of 12, a selective KHK inhibitor with potency and properties
suitable for evaluating KHK inhibition in rat models. Key structural
features interacting with KHK were discovered through fragment-based
screening and subsequent optimization using structure-based drug design,
and parallel medicinal chemistry led to the identification of pyridine 12.