Sortilin-binding small molecules for increasing glucose uptake
Inventors
Patel, Niketa A. • Sparks, Robert Pleasants • Guida, Wayne Charles
Assignees
US Department of Veterans Affairs • University of South Florida St Petersburg
Publication Number
US-10849896-B2
Publication Date
2020-12-01
Expiration Date
2036-05-10
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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 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.
Core Innovation
This invention identifies various scaffolds of small molecules capable of binding to the active site of sortilin to increase glucose uptake. The key scaffolds include norbornene anhydride amino acid adducts and 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxalines. These sortilin ligands have been demonstrated to increase the uptake of glucose in 3T3L1 cells and can be employed in compositions to enhance glucose uptake for treating diabetic patients.
The problem addressed by this invention arises from the role of sortilin in glucose regulation and its decreased expression in diabetic and obese individuals. Sortilin is a critical component in insulin-responsive transport systems, particularly for Glut4-containing vesicles in adipocytes, which mediate glucose uptake. Diabetic patients exhibit insulin resistance, largely because glucose transport is impaired. Sortilin levels are decreased in obese diabetic humans, and this decrease contributes to defects in glucose transport and insulin resistance. Therefore, there is a need for compounds that stabilize sortilin to correct these glucose transport defects and address obesity in diabetic patients.
The invention provides compounds identified via in silico docking methods that bind to the active site of sortilin with high affinity. These compounds promote increased glucose uptake in adipocytes by stabilizing sortilin, as demonstrated through in vitro testing with murine 3T3L1 adipocytes, which serve as a model for studying adipogenesis and glucose transport relevant to human obesity and diabetes. The compounds belong to three scaffolds chosen for their ability to permeate cell membranes and reach intracellular sortilin, thus enhancing glucose uptake and sortilin expression at the protein level without affecting sortilin mRNA levels.
Claims Coverage
The patent discloses one independent claim focused on a method of treating diabetic patients using specific sortilin-binding compounds.
Method of treating diabetes by administering 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxaline compounds
The method comprises administering a pharmaceutical composition containing a vehicle and a 2-substituted 3-oxo-1,2,3,4-tetrahydro-2-quinoxaline compound effective to stabilize sortilin and increase blood glucose uptake in diabetic patients.
The claims cover administering specific sortilin-binding compounds formulated with pharmaceutically acceptable vehicles to treat diabetes by stabilizing sortilin and enhancing glucose uptake.
Stated Advantages
The compounds function to stabilize sortilin and promote glucose uptake in adipocytes.
They can correct defects in glucose transport associated with obesity and diabetes.
The scaffolds have suitable physicochemical properties to permeate cell membranes and act intracellularly.
Documented Applications
Use of the identified sortilin-binding small molecules to increase glucose uptake in adipocytes for the treatment of diabetic patients.
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