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Publication Number
US-11202789-B2
Publication Date
2021-12-21
Expiration Date
Abstract
The present disclosure provides methods and compositions for the treatment of hepatic symptoms of glycogen storage diseases through the administration of thyroid hormone receptor agonists. The methods and compositions provided herein are useful in the treatment of hyperlipidemia, hypercholesterolemia, hepatic steatosis, cardiomegaly, hepatomegaly, hepatic fibrosis, and cirrhosis associated with glycogen storage diseases (GSD) and defects of glycogen metabolism. Said compounds may also be useful in the prevention of GSD-related hepatocellular adenoma and hepatocellular carcinoma.
Core Innovation
The disclosed subject matter provides compound structures for treatment of glycogen storage disease Ia (GSD-Ia). The described candidate compounds include thyroid hormone receptor-beta (TRβ) agonist or prodrug compounds and phosphorus-based groups, such as phosphonate, phosphinate, or phosphate-containing substituents, attached to aromatic or polyaromatic rings, with various halogen and substituent patterns.
The structures include stereoisomers, analogs, and pharmaceutically acceptable salts, with substituents such as chlorine, bromine, fluorine, iodine, and heteroatom substitutions including nitrogen and sulfur. Selected variants include phenolic OH, ether-linked biaryl scaffold features, carboxylate or ester substituents, and stereochemical forms such as cis/trans.
A method is provided for treating glycogen storage disease Ia by administering to a subject a compound having the specified structure, or a pharmaceutically acceptable salt thereof. The treatment is further described as ameliorating disease-related conditions associated with GSD-Ia, including a glycogen storage defect and associated hepatic conditions, and is associated with pharmaceutical compositions and pharmaceutical dosing forms.
Claims Coverage
The claims include an independent method claim directed to treating glycogen storage disease Ia (GSD-Ia) by administering a compound having a specified chemical structure, or a pharmaceutically acceptable salt. Dependent claims add five recurring inventive refinements involving treatment context and disease-related outcomes.
Treating glycogen storage disease Ia with a specified compound
A method of treating glycogen storage disease Ia (GSD-Ia), comprising administering to a subject in need thereof a compound having the structure, or a pharmaceutically acceptable salt thereof.
Ameliorating a glycogen storage defect
The method provides administering a compound that ameliorates a glycogen storage defect.
Ameliorating hepatic steatosis, hypercholesterolemia, or hepatic inflammation
The method covers administering a compound that ameliorates hepatic steatosis, hypercholesterolemia, or hepatic inflammation in connection with a glycogen storage disease.
Administering together with a liver, kidney, or bone marrow transplant
The method administers the compound together with a liver, kidney, or bone marrow transplant.
Reducing body mass, liver mass metrics, or liver triglyceride levels
The method is characterized in that administering the compound reduces body mass, liver mass, the liver mass expressed as a percentage of body mass, or liver triglyceride levels.
Using a second therapeutic agent selected from starches
The method uses a second therapeutic agent selected from corn starch, potato starch, wheat starch, vegetable starch, and cassava, or combinations thereof.
Overall, the claim set centers on administering a structurally specified compound, or a pharmaceutically acceptable salt, to treat GSD-Ia, with refinements specifying amelioration of glycogen storage defects and related hepatic conditions, optional transplant-associated context, reductions in body and liver metrics or triglycerides, and combination with specific starch-based second therapeutic agents.
Stated Advantages
Reduces cholesterol, liver triglycerides, steatosis, liver mass, body mass, serum cholesterol, and triglycerides.
Modulates blood glucose in GSD models.
Improves hepatic pathology.
Treating glycogen storage disease Ia (GSD-Ia).
Ameliorating a glycogen storage defect.
Ameliorating hepatic steatosis, hypercholesterolemia, or hepatic inflammation.
Reducing body mass, liver mass, liver mass expressed as a percentage of body mass, or liver triglyceride levels.
Documented Applications
Treating glycogen storage disease Ia (GSD-Ia) in a subject in need thereof by administering a compound having the specified structure, including a TRβ agonist or phosphonic-acid-containing compound, or a pharmaceutically acceptable salt.
Treating associated hepatic and non-hepatic metabolic symptoms in connection with glycogen storage diseases, including hepatic steatosis and hypercholesterolemia.
Use in association with liver, kidney, or bone marrow transplant.
A method of treating glycogen storage disease Ia (GSD-Ia) in a subject in need thereof by administering a compound having the specified structure or a pharmaceutically acceptable salt thereof.
The method as part of administration together with a liver, kidney, or bone marrow transplant.
A method in which administration reduces body mass, liver mass/liver mass percentage, or liver triglyceride levels in the context of glycogen storage disease.
A method for ameliorating hepatic steatosis, hypercholesterolemia, or hepatic inflammation associated with glycogen storage disease.
A method that uses a second therapeutic agent selected from corn starch, potato starch, wheat starch, vegetable starch, and cassava, or combinations thereof.
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