Sortilin-binding small molecules for increasing glucose uptake
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 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.
1. A method of treating a diabetic patient, comprising:
administering a pharmaceutical composition to a diabetic patient in an amount effective to stabilize sortilin and increase blood glucose uptake in said patient;
wherein the pharmaceutical composition comprises a vehicle for administration to a patient, and a 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxaline compound of formula (I),
where x is H, C1-C5 alkyl, acyl, amino, chloro, bromo, iodo, or fluoro and where the carboxylic acid may be separated from the ring by one to three carbons which may be substituted with a C1 to C5 alkyl.
2. The method of claim 1 , wherein administration occurs intravenously, orally, rectally, sublingually, sublabially, epidurally, intracerebrally, intracerebroventrically, topically, nasally, intervitrally, subcutaneously, transdermally, or by inhalation.
3. The method 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.
4. The method 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.