Sortilin-Binding Small Molecules for Increasing Glucose Uptake

Abstract

Various scaffolds of small molecules capable of binding to the active site of sortilin are identified by in silico methods. These scaffolds include norbornene anhydride amino acid adducts, phenyl-amide-acids of benzyl substituted glutaric acids, and 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxalines. These sortilin ligands increase the uptake of glucose in 3T3L1 cells and can be employed in compositions to increase uptake of glucose for the treatment of diabetic patents.

We claim: 
     
         1 . A composition for the stabilization of sortilin and increase of glucose uptake, comprising at least one small molecule selected from the scaffolds consisting of norbornene anhydride amino acid adducts, phenyl-amide-acids of benzyl substituted glutaric acids, and 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxalines, and a vehicle for administration to a patient. 
     
     
         2 . The composition of  claim 1 , wherein the norbornene anhydride amino acid adduct is selected from 2-methyl-3,5-dioxo-4-azatricyclo[5.2.1.0(2,6)]dec-8-en-4-yl)acetic acid, methyl 2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl)propanoate, 2-(1,3-dioxo-1,3,3a,4,7,7a-hexahydro-2H-4,7-methanoisoindol-2-yl)-4-(methylthio)butanoic acid, and 2-(3,5-dioxo-4-azatricyclo[5.2.1.0(2,6)]dec-8-en-4-yl)-4-methylpentanoic acid. 
     
     
         3 . The composition of  claim 1 , wherein the phenyl-amide-acids of benzyl substituted glutaric acid is selected from 4-[(3,4-dichlorophenyl)amino]-3-(3-methylbenzyl)-4-oxobutanoic acid and 3-benzyl-4-[(3-chloro-2-methylphenyl)amino]-4-oxobutanoic acid. 
     
     
         4 . The composition of  claim 1 , wherein the 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxaline is (3-oxo-1,2,3,4-tetrahydro-2-quinoxalinyl)acetic acid. 
     
     
         5 . The composition of  claim 1 , wherein the vehicle for administration comprises one or more solvents, buffering agents, transporters, salts, binders, fillers, disintegrants, lubricants, encapsulates, emulsifiers, suspending agents, penetration enhancers, flavoring agents, preservatives, propellants, and/or coloring agents. 
     
     
         6 . A method of treating a diabetic patent, comprising administration of a composition for the increase of glucose uptake according to  claim 1 . 
     
     
         7 . The method of  claim 6 , wherein administration occurs intravenously, orally, rectally, sublingually, sublabially, epidurally, intracerebrally, intracerebroventrically, topically, nasally, intervitrally, subcutaneously, transdermally, or by inhalation. 
     
     
         8 . A method for identification of a small molecule for stabilizing sortilin and increasing the glucose uptake according to  claim 1 , comprising in silico screening of the docking of a small molecule having a log p value indicative of good permeability through a cell membrane to the active site of sortilin, wherein the docking is assessed with a scoring of electrostatic interactions at amino acid residues: Serine 272, Arginine 292, Phenylalanine 273, Serine 283 and Tyrosine 318.