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-11084836-B2
Publication Date
2021-08-10
Expiration Date
2037-02-24
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Abstract
Lanthionine ketimine derivatives, and methods of making and using the same, are described. Included are lanthionine ketimine phosphonate (LK-P), lanthionine ketimine ester phosphonate (LKE-P) derivatives, as well as lanthionine ketimine derivatives having a tert-enamide moiety at the 2-position (NVP-LKE).
Core Innovation
The invention describes lanthionine ketimine derivatives, specifically lanthionine ketimine phosphonate (LK-P) and lanthionine ketimine ester phosphonate (LKE-P) compounds, as well as derivatives incorporating a tert-enamide moiety at the 2-position (NVP-LKE). These new compounds exhibit modified chemical structures, such as replacing the carboxylate at the C3 position with a phosphonate or phosphonate ester group, and introducing various lipophilic substituents at the C2 position. The compounds are designed to enhance potency and improve therapeutic properties related to modulating autophagy, especially in diseases where autophagy dysfunction is implicated.
The problem addressed by the invention is the lack of small molecule therapeutics suitable for clinically manipulating autophagy, which plays a critical role in cellular recycling and is relevant to more than 100 diseases, including neurodegenerative conditions. Current methods to enhance autophagy, such as starvation or rapamycin derivatives, are not practical for chronic disease treatment due to toxicity or poor brain penetration. Previous compounds like LK and LKE have shown promising activity, but there remains a need for molecules with improved stability, potency, and bioavailability.
The core innovation is the provision of LK-P, LKE-P, and NVP-LKE derivatives, which demonstrate greater stability and bioavailability by virtue of their altered chemical structures. The phosphonate substitution at C3 increases charge density, reducing decomposition and enhancing potency, while C2 lipophilic substitutions promote blood brain barrier permeability. The derivatives are capable of stimulating autophagy as shown in cellular assays, and NVP-LKE in particular is indicated to be as potent or more potent than LKE for modulating neuroinflammatory responses and autophagy. These compounds are further formulated into pharmaceutical compositions or used in methods for treating, preventing, or ameliorating autophagy-related diseases.
Claims Coverage
There are three main independent inventive features described in the patent.
Lanthionine ketimine phosphonate (LK-P) or lanthionine ketimine ester phosphonate (LKE-P) compounds of Formula D
A compound comprising Formula D, where: - R1 is hydrogen or a substituted or unsubstituted alkyl, aryl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido. - R2 is hydrogen or a substituted or unsubstituted alkyl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido. - R3 is hydrogen, or a substituted or unsubstituted alkyl, aryl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido. - X is hydrogen, a group I metal, a halide, or a substituted or unsubstituted alkyl, alkoxy, ester, alkenylamino, alkynylamino, aryloxy, aralkoxy, acyloxy, alkylamino, arylamino, aralkylamino, or amido.
Method of treating or ameliorating autophagy-related diseases using 2-isopropyl lanthionine ketimine phosphonate (LK-P)
A method for treating or ameliorating at least one of an autophagy-related disease selected from glioma and Parkinson's disease, comprising administering an effective amount of 2-isopropyl lanthionine ketimine phosphonate (LK-P) having Formula IX, or other specified compounds with histone deacetylase inhibitory activity.
Pharmaceutical composition comprising LK-P or LKE-P compounds
A pharmaceutical composition that contains an effective amount of a compound of Formula D (LK-P or LKE-P) and a pharmaceutically acceptable carrier, diluent, or adjuvant.
The claims cover structurally defined LK-P and LKE-P compounds, methods of treating autophagy-related diseases with these compounds—especially specific forms like 2-isopropyl LK-P—and pharmaceutical compositions comprising these compounds and acceptable carriers.
Stated Advantages
The phosphonate derivatives exhibit greater stability due to reduced susceptibility to oxidative decarboxylation compared to carboxylate forms.
These compounds demonstrate better bioavailability relative to previous lanthionine ketimine derivatives.
The phosphonate and phosphonate ester analogues have increased potency as autophagy enhancers due to increased charge density.
Hydrophobic substitutions at the C2 position enhance blood brain barrier permeability.
The new derivatives retain neuroprotective activity and are effective in stimulating autophagy in cellular assays.
The NVP-LKE derivatives are as potent or more potent than LKE for suppressing microglial activation and stimulating autophagy.
Documented Applications
Treatment and/or prevention of autophagy-related diseases, including neurodegenerative diseases such as ALS, Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis.
Treatment, prevention, or amelioration of inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease.
Reduction of damage to cells resulting from oxidative stress, excitotoxicity, free radical toxicity, or excitatory amino acid toxicity, especially in neurons, macrophages, or glial cells.
Treatment or prevention of cancers, including cancer of 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 or prevention of diseases characterized by excessive nitric oxide or prostaglandin formation, or overexpression of iNOS or COX-2 gene.
Use in pharmaceutical compositions for various routes of administration, including oral, intravenous, intradermal, and topical.
Preparation of kits for making LK-P, LKE-P, or NVP compounds.
Treatment for neurodegenerative diseases wherein protein delivery to lysosomes is compromised, such as Batten disease, Niemann-Pick disease, Machado-Joseph disease, spinocerebellar ataxia, Fabry disease, and mucopolysaccharoidosis.
Treatment of stroke and stroke-related complications in human subjects.
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