Ketohexokinase (KHK, also known as fructokinase) catalyzes, with adenosine triphosphate (ATP) and potassium ion (K+), the conversion of furanose form of D-fructose to fructose-1-phosphate. It initiates the intracellular catabolism of a large proportion of dietary carbohydrate and is an important regulator of hepatic glucose metabolism. Due to its role in dietary fructose metabolism, inhibition of KHK's activity would suppress carbon supply for fatty acid and very low density lipoprotein synthesis. Hence, modulation of KHK will help relieve the aforementioned metabolic disturbances making KHK an important target in drug discovery. We described herein a novel series of indazoles as KHK inhibitors from a pyrazole hit identified through fragment-based drug discovery (FBDD). The optimization process guided by both X-ray crystallography and solution activity resulted in lead-like compounds with good pharmaceutical properties.

Discovery of a novel series of indazoles as ketohexokinase inhibitors through a pyrazole hit from FBDD

244th National Meeting (2012)

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