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-12139505-B2
Publication Date
2024-11-12
Expiration Date
2038-02-16
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Lanthionine ketimine phosphonate (LK-P), lanthionine ketimine ester phosphonate (LKE-P), other lanthionine ketimine, lanthionine ketimine phosphonate, and lanthionine ketimine ester derivatives, methods of making and using the same, and methods of treatments are described.
Core Innovation
The invention provides lanthionine ketimine derivatives in which the carboxylic acid group at the 3-position of a 1-thia-4-aza-2-cyclohexene ring is replaced with a phosphonate group or a phosphonate ester group, or in which the 2-position is independently substituted, resulting in new compounds termed LK-P, LKE-P, LK-PE, and LKE-PE. These compounds retain or improve upon the neuroprotective activity of prior lanthionine ketimine derivatives and are capable of crossing cellular membranes including the blood-brain barrier. The compounds are described in multiple generic structural formulas (including Formulas F, D, and E), allowing a wide scope of substituents at positions R1, R2, and R3, with specific exclusions for known compounds.
The problem addressed by this invention is the lack of small molecule therapeutics that modulate autophagy, a critical catabolic process involved in various diseases, particularly neurodegenerative and inflammatory conditions. Conventional approaches to enhance autophagy, such as starvation or rapamycin derivatives, are deemed impractical for chronic disease due to either impracticality or toxicity and poor brain penetration. Previously described compounds (e.g., LK and LKE) showed some efficacy but left unmet needs for stability, potency, and bioavailability.
This invention solves the problem by introducing phosphonate or phosphonate ester substitution at the 3-position, increasing charge density and improving compound stability against oxidative decarboxylation. Hydrophobic substituents at the 2-position enhance potency and permeability, especially across the blood-brain barrier. Experimental data demonstrate that these phosphonate analogues and C2-substituted derivatives are potent stimulators of cellular autophagy, show enhanced neuroprotective effects, and can be formulated into pharmaceutical compositions. The patent further provides methods of synthesis, compositions, and diverse methods of treatment for autophagy-related diseases.
Claims Coverage
The claims disclose multiple inventive features centered around new chemical compounds, compositions, and methods of treatment.
Compound of Formula F with defined substituent groups
A compound comprising Formula F, wherein: - R1 is hydrogen or substituted/unsubstituted alkyl, aryl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido; - R2 is selected from COOH, COOR4, PO(OH)2, PO(OR4)2, POOR4OR5, and POOR4OX (with further definitions for R4, R5, and X); - R3 is hydrogen or substituted/unsubstituted alkyl, aryl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido; with an explicit proviso that when R1 is hydrogen and R2 is COOH, R3 is not ethyl or hydrogen.
Pharmaceutical composition comprising the claimed compound
A pharmaceutical composition comprising: - a therapeutically effective amount of a compound as defined above (of claim 1); - a pharmaceutically acceptable carrier, diluent, or adjuvant.
The inventive features protected are the structural definition of novel lanthionine ketimine derivatives with specified substituent variability and their composition as pharmaceutical agents.
Stated Advantages
The compounds offer greater stability compared to carboxylate analogs due to resistance to oxidative decarboxylation and reduced dimerization.
The phosphonate and ester derivatives exhibit improved potency in stimulating autophagy compared to previously known compounds.
Enhanced bioavailability is provided by phosphonate analogs and further improved with hydrophobic C2 substituents for better blood-brain barrier permeability.
The compounds maintain therapeutic activity and neuroprotective properties and can be formulated for various routes of administration.
Documented Applications
Treatment of autophagy-related diseases, including neurodegenerative diseases such as ALS, Alzheimer's disease, Huntington's disease, Parkinson's disease, multiple sclerosis, macular degeneration, and Batten disease.
Treatment of inflammatory diseases, including rheumatoid arthritis and inflammatory bowel disease.
Reduction of cellular damage due to oxidative stress, excitotoxicity, free radical toxicity, or excitatory amino acid toxicity in neurons, macrophages, or glial cells.
Treatment of cancer, including 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 cancers.
Treatment of patient pathologies involving excessive production of nitric oxide or prostaglandins, disorders characterized by iNOS or COX-2 gene overexpression, and modulation of excessive nitric oxide or prostaglandin formation.
Treatment of subjects at risk for or experiencing a stroke.
Treatment for neurodegenerative diseases wherein protein delivery to lysosomes is compromised, including Niemann-Pick disease, Machado-Joseph disease, spinocerebellar ataxia, Fabry disease, and mucopolysaccharoidosis.
Reduction in proliferative capacity of glioma cells in culture and rescue of cells from tumor necrosis factor alpha (TNFa) toxicity.
Interested in licensing this patent?