Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site

Attenuation of fructose metabolism by the inhibition of ketohexokinase (KHK; fructokinase) should reduce body weight, free fatty acids, and triglycerides, thereby offering a novel approach to treat diabetes and obesity in response to modern diets. We have identified potent, selective inhibitors of human hepatic KHK within a series of pyrimidinopyrimidines (<b>1</b>). For example, <b>8</b>, <b>38</b>, and <b>47</b> exhibited KHK IC<sub>50</sub> values of 12, 7, and 8 nM, respectively, and also showed potent cellular KHK inhibition (IC<sub>50</sub> < 500 nM), which relates to their intrinsic potency vs KHK and their ability to penetrate cells. X-ray cocrystal structures of KHK complexes of <b>3</b>, <b>8</b>, and <b>47</b> revealed the important interactions within the enzyme's adenosine 5'-triphosphate (ATP)-binding pocket.