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ACS Med Chem Lett. 2011 Apr 18;2(7):538-43. doi: 10.1021/ml200070g. eCollection 2011 Jul 14.

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

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1
Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.

Erratum in

  • ACS Med Chem Lett. 2012 Mar 8;3(3):263.

Abstract

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 (1). For example, 8, 38, and 47 exhibited KHK IC50 values of 12, 7, and 8 nM, respectively, and also showed potent cellular KHK inhibition (IC50 < 500 nM), which relates to their intrinsic potency vs KHK and their ability to penetrate cells. X-ray cocrystal structures of KHK complexes of 3, 8, and 47 revealed the important interactions within the enzyme's adenosine 5'-triphosphate (ATP)-binding pocket.

KEYWORDS:

Kinase; crystal structure; diabetes; fructose metabolism; obesity

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