Compositions useful in therapy of autophagy-related pathologies, and methods of making and using the same
Inventors
Hensley, Kenneth • Denton, Travis
Assignees
University of Toledo • Washington State University WSU
Publication Number
US-10882831-B2
Publication Date
2021-01-05
Expiration Date
2038-02-16
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Abstract
Lanthionine ketimine phosphonate (LK-P), lanthionine ketimine ester phosphonate (LKE-P), other lanthionine ketimine, lanthionine ketimine phosphonate, and lanthionine ketimine ester derivatives, and methods of making and using the same, are described.
Core Innovation
The invention provides novel compounds that are derivatives of lanthionine ketimine, specifically lanthionine ketimine phosphonate (LK-P), lanthionine ketimine ester phosphonate (LKE-P), and related derivatives. These molecules are characterized by the replacement of the carboxylic acid group at the 3-position of the 1-thia-4-aza-2-cyclohexene ring with a phosphonate or phosphonate ester, or by modifications at the 2-position to include various lipophilic substituents. The compounds encompass a wide range of structural variations with different alkyl, aryl, and ester groups, along with salts, stereoisomers, racemates, hydrates, solvates, polymorphs, and alkene reduction products.
The core function of these compounds is to enhance autophagy, a cellular catabolic process essential for recycling macromolecules and organelles. The patent describes that autophagy dysfunction is implicated in over 100 diseases, particularly neurodegenerative conditions. Prior to this invention, small molecule therapeutics capable of safely and effectively targeting autophagy were lacking, with existing approaches associated with limited efficacy, chronic toxicity, or poor brain penetrance.
By strategically modifying the core lanthionine ketimine structure, the present invention delivers compounds that retain or improve therapeutic properties such as neuroprotection and autophagy induction while achieving better pharmacokinetic profiles, including increased blood-brain barrier transport. The disclosure also provides methods of synthesizing these compounds and their use in treating autophagy-related diseases, reducing cellular damage, and manufacturing pharmaceutical compositions.
Claims Coverage
There are several independent claims in this patent, each introducing key inventive features in the fields of novel chemical compounds, specific pharmaceutical compositions, synthetic methods, and therapeutic applications.
Novel lanthionine ketimine derivative compounds (Formula E)
A compound of Formula E, where R1 is alkyl or aryl; R2 is hydrogen or heteroatom substituted or unsubstituted alkyl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido; and R3 is substituted or unsubstituted alkyl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido. The claim also covers various specific substituents for R2 and R3, enabling a diverse set of chemical entities.
2-isopropyl-AECK-P compound
A compound comprising 2-isopropyl-AECK-P as specifically depicted by its structure, which is a defined aminomethyl cysteine ketimine phosphonate with isopropyl substitution.
Use of 2-ethyl-LKE or 2-n-hexyl-LKE-P for treating glioma
A method of treating a glioma by administering an effective amount of 2-ethyl-LKE or 2-n-hexyl-LKE-P to a subject in need thereof, wherein 'LKE' refers to a 5-ester of lanthionine ketimine compound and 'LKE-P' refers to a 5-ester of a lanthionine ketimine phosphonate compound.
Reducing cellular damage by lanthionine ketimine derivatives
A method comprising contacting a cell, including neuron, macrophage, or glial cell, with an LK, LKE, 2-isopropyl-AECK-P, 2-n-butyl LK-P, or 2-isopropyl LK-P compound, and reducing damage to the cell.
Synthetic method for 2-substituted lanthionine ketimine compounds
A method for making a compound of claim 1 by: 1. Reacting an enolate of a carboxylic acid ester with a dialkyl oxalate to produce a 2-substituted-3-oxosuccinate diester. 2. Hydrolyzing and decarboxylating the 2-substituted-3-oxosuccinate diester to produce an α-ketocarboxylic acid. 3. Either (i) directly brominating the α-ketocarboxylic acid followed by reaction with a cysteine derivative, or (ii) esterifying the α-ketocarboxylic acid followed by bromination and reaction with a cysteine derivative to produce a 2-substituted lanthionine ketimine compound.
The independent claims cover new lanthionine ketimine-based compounds with broad structural variability, their use in treating diseases such as glioma, compositions for reducing cellular damage, specific synthetic routes, and notably the 2-isopropyl-AECK-P compound, providing broad coverage for therapeutic and manufacturing applications.
Stated Advantages
Phosphonate derivatives have greater stability compared to carboxylate analogs, as they are not subject to oxidative decarboxylation and resultant decomposition.
Compounds exhibit improved bioavailability due to structural modification, especially with hydrophobic substituents enhancing blood-brain barrier permeability.
The replacement of carboxylate with phosphonate at the 3-position increases potency and improves compound stability.
Hydrophobic substituents on the core structure enhance potency by increasing interactions with biological binding partners and membrane penetration.
The compounds successfully retain or enhance autophagy-promoting and neuroprotective activity relative to known lanthionine ketimine and its ester derivatives.
Documented Applications
Treatment of autophagy-related diseases, including ALS, Alzheimer's disease, Huntington's disease, Parkinson's disease, stroke, multiple sclerosis, macular degeneration, atherosclerosis, rheumatoid arthritis, inflammatory bowel disease, attention deficit disorder, depression, and generalized anxiety disorder.
Reduction of damage to neurons, macrophages, or glial cells resulting from oxidative stress, excitotoxicity, free radical toxicity, or excitatory amino acid toxicity.
Treatment of inflammatory diseases, specifically rheumatoid arthritis and inflammatory bowel disease.
Treatment of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, ALS, and Huntington's disease.
Treatment of pathogenesis involving excessive production of nitric oxide or prostaglandins.
Treatment of disorders characterized by the overexpression of iNOS or COX-2 genes.
Modulation of transcription or translation of iNOS or COX-2 genes in a patient.
Modulation of excessive nitric oxide or prostaglandin formation.
Treatment of subjects having, or at risk for, stroke.
Treatment of cancer, including cancers of the brain, lung, liver, spleen, kidney, lymph node, small intestine, pancreas, blood cell, bone, colon, stomach, endometrium, prostate, testicle, ovary, central nervous system, skin, head and neck, esophagus, or bone marrow.
Treatment of neurodegenerative diseases wherein protein delivery to lysosomes is compromised, including Batten disease, Niemann-Pick disease, Machado-Joseph disease, spinocerebellar ataxia, Fabry disease, and mucopolysaccharoidosis.
Use in methods for making the described compounds and kits for manufacturing autophagy stimulator compounds.
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