title: Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site.
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.
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: John C
authors.initials: JC
authors.lastname: O'Neill
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Yabut
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: Diane K
authors.initials: DK
authors.lastname: Luci
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: Alfonzo D
authors.initials: AD
authors.lastname: Jordan
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: John A
authors.initials: JA
authors.lastname: Masucci
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: William J
authors.initials: WJ
authors.lastname: Jones
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: Marta C
authors.initials: MC
authors.lastname: Abad
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: Alan C
authors.initials: AC
authors.lastname: Gibbs
authors.affiliation: Johnson & Johnson Pharmaceutical Research & Development , Spring House, Pennsylvania 19477-0776, United States.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Petrounia
keywords: Kinase; crystal structure; diabetes; fructose metabolism; obesity