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

Abstract

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.

Metabolic Targets in Nonalcoholic Fatty Liver Disease

“…Fructose is a more potent inducer of DNL than glucose 34 and chronic fructose consumption induces activation of SREBP1c and ChREBP and downstream lipogenic gene transcription 31 . Thus, strategies aimed at directly inhibiting fructose metabolism (ie, ketohexokinase inhibition 35 or limiting fructose consumption in the diet) represent attractive therapeutic approaches for NAFLD and NASH.…”

Discovery of Orally Bioavailable Selective Inhibitors of the Sodium-Phosphate Cotransporter NaPi2a (SLC34A1)

“…A literature method was used to synthesize compounds 4a−b. 30 Standard S N Ar chemistry was used to install a 7-amino group on the azaindole core, leading to compounds 3a−c. Alternatively, chlorination of the azaindole at the 3-position was effected with N-chlorosuccinimide to a IC 50 's and K i 's are reported as the geometric mean of n ≥ 3 ± standard error of the mean, except where otherwise noted.…”

Evolving Role for Pharmacotherapy in NAFLD/NASH

“…42,43 More recently, Pfizer developed a potent reversible inhibitor of human KHK. 44 In a phase II study of 53 subjects with NAFLD (> 6% liver fat assessed by MRI-PDFF), subjects received either placebo or the KHK inhibitor PF-06835919 at 75 or 300 mg of once daily dosing for 6 weeks (NCT03256526). Participants treated with 300 mg of KHK inhibitor showed a 26.5% reduction in PDFF (P = 0.039) from baseline as compared with the placebo group.…”

“…Small molecule inhibitors of KHK have been of interest to pharmaceutical industry for a long time, but initial KHK inhibitors lacked specificity 42,43 . More recently, Pfizer developed a potent reversible inhibitor of human KHK 44 . In a phase II study of 53 subjects with NAFLD (> 6% liver fat assessed by MRI‐PDFF), subjects received either placebo or the KHK inhibitor PF‐06835919 at 75 or 300 mg of once daily dosing for 6 weeks (NCT03256526).…”