Development of Dihydroxyphenyl Sulfonylisoindoline Derivatives as Liver-Targeting Pyruvate Dehydrogenase Kinase Inhibitors

Pyruvate
dehydrogenase kinases 1–4 (PDK1–4) negatively
control activity of the pyruvate dehydrogenase complex (PDC) and are
up-regulated in obesity, diabetes, heart failure, and cancer. We reported
earlier two novel pan-PDK inhibitors PS8 [4-((5-hydroxyisoindolin-2-yl)­sulfonyl)­benzene-1,3-diol]
(1) and PS10 [2-((2,4-dihydroxyphenyl)­sulfonyl)­isoindoline-4,6-diol]
(2) that targeted the ATP-binding pocket in PDKs. Here,
we developed a new generation of PDK inhibitors by extending the dihydroxyphenyl
sulfonylisoindoline scaffold in 1 and 2 to
the entrance region of the ATP-binding pocket in PDK2. The lead inhibitor
(S)-3-amino-4-(4-((2-((2,4-dihydroxyphenyl)­sulfonyl)­isoindolin-5-yl)­amino)­piperidin-1-yl)-4-oxobutanamide
(17) shows a ∼8-fold lower IC50 (58
nM) than 2 (456 nM). In the crystal structure, the asparagine
moiety in 17 provides additional interactions with Glu-262
from PDK2. Treatment of diet-induced obese mice with 17 resulted in significant liver-specific augmentation of PDC activity,
accompanied by improved glucose tolerance and drastically reduced
hepatic steatosis. These findings support 17 as a potential
glucose-lowering therapeutic targeting liver for obesity and type
2 diabetes.