Methods and Compositions for the Inhibition of Fructokinase

• US 20130224218A1
• Filed: 08/08/2011
• Published: 08/29/2013
• Est. Priority Date: 08/06/2010
• Status: Active Grant

• Current Assignee: University of Colorado System
• Original Assignee: The Board of Regents of the University of Colorado (University of Colorado System)
• Inventors: Johnson, Richard J., Lanaspa, Miguel A., Ishimoto, Takuji
• Granted Patent: US 9,387,245 B2
• Time in Patent Office: Days
• US Class Current: 424/158.1
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/415 1,2-Diazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/7052 having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
• CPC Class Codes: A61K 38/005 Enzyme inhibitors protease inhibitors A61K38/55
• CPC Class Codes: A61K 39/39533 against materials from animals
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 16/40 against enzymes
• CPC Class Codes: C12N 15/1137 against enzymes viral enzymes C12N15/1131; receptors C12N15/1138
• CPC Class Codes: C12N 9/1205 Phosphotransferases with an alcohol group as acceptor (2.7.1), e.g. protein kinases

Abstract

The invention relates to the use of isoform-specific fructokinase (ketohexokinase) (KHK) inhibitors alone or in combination with various agents to both prevent and treat a wide variety of diseases including, but not limited to, sugar craving, obesity, features of metabolic syndrome (including insulin resistance, hypertriglyceridemia, hypertension, and fatty liver), polyuria, proximal tubular injury, and diabetic kidney disease.

Claims

1-109. -109. (canceled)

110. A method for diminishing, inhibiting or eliminating addiction-related behavior of a mammal, wherein said method comprises administering to said mammal an effective amount of a composition comprising a KHK-C inhibitor, and wherein the addiction-related behavior is associated with a compulsion for fructose and/or sucrose intake.

111. A composition useful for decreasing a craving for fructose and/or a fructose-containing compound, said composition comprising a KHK-C inhibitor.

112. The composition of claim 111, wherein said KHK-C inhibitor is a combination KHK-A and KHK-C inhibitor.

113. The composition of claim 111, wherein said KHK-C inhibitor comprises a member from the group consisting of a ribozyme, an interfering molecule, peptide nucleic acid, peptide, small molecule, an antibody targeted to KHK-C, and combinations thereof.

114. The composition of claim 111, wherein the composition further comprises a conjunctive therapeutic compound.

115. A method for reducing ATP depletion and/or intrarenal uric acid production in a subject, the method comprising inhibiting KHK-C in the subject, wherein said inhibiting comprises administering a composition of claim 111.

116. The method of claim 115, wherein the inhibiting comprises administering a KHK-C inhibitor to the subject.

117. The method of claim 115, wherein the KHK-C inhibitor inhibits KHK-C, but does not inhibit KHK-A.

118. The method of claim 115, wherein the KHK-C inhibitor comprises at least one member of the group consisting of a ribozyme, an interfering molecule, a peptide, a small molecule, or an antibody targeted to KHK-C.

119. The method of claim 118, wherein the KHK-C inhibitor comprises an interfering molecule, and wherein the interfering molecule comprises a member from the group consisting of a phosphothioate morpholino oligomer (PMO), miRNA, sRNA, methylated sRNA, treated siRNAs, shRNA, antisense RNA, a dicer-substrate 27-mer duplex, and any combination thereof.

120. The method of claim 115, wherein the administering is done to treat or prevent acute kidney injury (AKI) associated with administration of a contrast agent.

121. The method of claim 115, wherein the administering is done to treat or prevent AKI associated with cardiovascular surgery, IgG administration, or sepsis.

122. The method of claim 115, wherein the administering is done to treat or prevent acute tubular injury.

123. The method of claim 115, wherein the administering is done to treat or prevent a disorder selected from the group consisting of attention deficit disorder, sugar addiction, obesity, and metabolic syndrome.

124. The method of claim 115, wherein the administering is done to provide a diminished craving in the subject from a member selected from the group consisting of fructose, fructose-containing sugars, and combinations thereof.

125. The method of claim 115, further comprising administering to the subject a conjunctive agent, wherein the conjunctive agent comprises a compound selected from the group consisting of angiotensin-converting enzyme (ACE) inhibitors, aldosterone antagonists, amphetamines, amphetamine-like agents, Angiotensin II receptor antagonists, anti-oxidants, aldose reductase inhibitors, biguanides, sorbitol dehydrogenase inhibitors, thiazolidinediones (glitazones), thiazide and thiazide-like diuretics, triglyceride synthesis inhibitors, xanthine oxidase inhibitors, and combinations thereof.

126. The method of claim 115, wherein the administering is done to treat diabetic polyuria.

127. A method of treating diabetic nephropathy in a subject, said method comprising administering a KHK-C inhibitor to the subject.