Gingerenone A prodrugs as sensotherapeutics and methods of use
Inventors
Moaddel, Ruin • Ferrucci, Luigi • Abdelmohsen, Kotb • Gorospe, Myriam • Rossi, Martina • Ramsden, Christopher E. • Keyes, Gregory S.
Assignees
US Department of Health and Human Services
Publication Number
US-12325688-B2
Publication Date
2025-06-10
Expiration Date
2043-01-17
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Abstract
Gingerenone A prodrug compounds have a structure according to Formula I, or a pharmaceutically acceptable salt thereof wherein one of R1 and R2 is H or —C(O)—R and the other of R1 and R2 is —C(O)—R. Each R independently is RA or, where RA is C18-C22 alkenyl, and RB is an amino acid side chain. The compounds are useful for inhibiting or eliminating senescence. The compounds may be administered to a subject having a senescence-associated disease or disorder, neuroinflammation, pain, and/or an amino acid deficiency.
Core Innovation
The invention concerns gingerenone A prodrugs having a structure according to Formula I or pharmaceutically acceptable salts thereof, wherein one of R1 and R2 is H or —C(O)—R and the other is —C(O)—R, with each R independently being RA or comprising an amino acid side chain RB. RA is a C18-C22 alkenyl group, often including two or more double bonds, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). The prodrugs are designed to be cleaved in vivo to provide gingerenone A and corresponding alkenyl compounds and/or amino acids, which may have therapeutic benefits including senolytic or senomorphic activity, neuroinflammation and pain reduction.
The problem addressed by the invention arises from cellular senescence, a state of permanent cell cycle arrest that accumulates with aging and promotes inflammation, tumorigenesis, and age-related pathologies. While senescence is beneficial in young organisms, its accumulation in older age is detrimental. Existing senolytic drugs selectively eliminate senescent cells and have shown improvement in age-related phenotypes, but only very few senotherapeutic compounds have been identified. Gingerenone A is a natural polyphenol with senolytic activity, but it suffers from limited bioavailability and stability, which hinders its therapeutic use.
To solve this, the invention provides gingerenone A prodrugs with one or two alkenyl ester groups that improve bioavailability, increase stability (such as shelf-life), and/or increase half-life compared to gingerenone A or alkenyl compounds alone. The prodrug structure may prevent oxidation of the polyunsaturated fatty acid components and exhibit synergistic therapeutic benefits. The prodrugs are useful for inhibiting or eliminating senescence, neuroinflammation, pain, and treating various senescence-associated or age-related diseases and disorders by acting as senolytic or senomorphic agents.
Claims Coverage
The claims include eight independent inventive features related to compounds, compositions, and methods of use involving gingerenone A prodrugs and their therapeutic effects.
Compound structure with specific R1 and R2 substituents
A compound having a structure according to Formula I or stereoisomers, tautomers, or pharmaceutically acceptable salts, where one of R1 and R2 is H or —C(O)—R and the other is —C(O)—R, with each R independently being C18-C22 alkenyl.
Compounds with R1 and R2 as —C(O)—RA groups
Compounds wherein R1 and R2 are —C(O)—RA, each RA independently being C18-C22 alkenyl, or where one of R1 and R2 is —C(O)—RA and the other is a specified amino acid moiety.
RA groups with multiple double bonds
Compounds where RA comprises two or more double bonds within the C18-C22 alkenyl chain.
Compounds with specified RB amino acid side chains
Compounds where RB is selected from amino acid side chains including —(CH2)4NH2, —CH3, —CH(CH3)2, —CH(CH3)CH2CH3, —CH2CH(CH3)2, —(CH2)2SCH3, —CH2OH, —CH(OH)CH3, —CH2C(O)NH2, —(CH2)2C(O)NH2, —CH2SH, —CH2NH2, —(CH2)3N(H)C(═NH)NH2, —CH2COOH, or —(CH2)2COOH.
Specific alkenyl ester groups for R1 and R2
Compounds where R1 and R2 independently are —C(O)—(CH2)3—(CH═CH—CH2)5—CH3 or —C(O)—(CH2)2—(CH═CH—CH2)6—CH3.
Compound with one R substitution as an amino acid moiety
Compounds where one of R1 and R2 is an amino acid moiety and the other is an alkenyl ester group as defined.
Specific exemplary compound structures
Compounds specifically exemplified having the defined Formula I with particular R1 and R2 substituents as described in the patent.
Pharmaceutical composition including the compound
Pharmaceutical compositions comprising the described gingerenone A prodrug compounds and a pharmaceutically acceptable carrier.
Method of inhibiting senescence by contacting cells
Methods for inhibiting senescence comprising contacting a senescent cell with an effective amount of the gingerenone A prodrug or a pharmaceutical composition containing it.
Senescence inhibition mechanisms
Inhibition of senescence by killing senescent cells, activating caspase-3, or both, optionally involving in vivo cleavage of the prodrug to provide gingerenone A and hydroxyalkyl components.
Method of treating senescence, neuroinflammation, pain in subjects
Methods of treating senescence, neuroinflammation, pain, or combinations thereof by administering therapeutically effective amounts of the gingerenone A prodrug or compositions.
Treatment effects on biomarkers and symptoms
Administration selectively kills senescent cells, activates caspase-3, reduces IL-6, CCL2, IP-10 secretions, increases IL-10, IL-13, raises circulating EPA, DHA, 17-hydroxydocosahexanoic acid, and reduces neuroinflammation and pain.
Treatment of various diseases and disorders associated with senescence
Application in subjects having senescence-associated, age-related, neurological, inflammatory, proliferative, metabolic, pulmonary, renal, eye, dermatologic diseases or disorders, and various examples thereof.
Administration routes
Administration via oral, parenteral, intramuscular, subcutaneous, topical, sublingual, intraocular, intranasal, inhalation, intrarectal, or intra-aural routes.
In vivo cleavage of compounds following administration
Upon administration, the compounds may be cleaved in vivo to yield gingerenone A, R1OH, and R2OH.
The claims cover novel gingerenone A prodrug compounds with specified alkenyl and amino acid substituents, their pharmaceutical compositions, and methods of using these compounds to inhibit senescence and treat associated diseases by mechanisms including senolytic and senomorphic activities, with administration via multiple routes and beneficial biomarker and symptom modulation.
Stated Advantages
Increased bioavailability of gingerenone A compared to gingerenone A alone.
Increased stability and shelf-life of the prodrugs relative to corresponding long-chain polyunsaturated fatty acids.
Potential synergistic therapeutic benefits when combining gingerenone A and alkenyl compounds.
Selectively kills senescent cells while sparing proliferating cells, with better selectivity than known senolytic cocktails.
Exhibits senomorphic effects by reducing pro-inflammatory cytokines and increasing anti-inflammatory cytokines.
Reduces neuroinflammation and decreases frequency and intensity of physical pain.
Documented Applications
Inhibiting or eliminating cellular senescence to improve age-associated diseases and functional declines.
Treatment of neuroinflammation and pain, including neuropathic pain and peripheral nerve injury.
Treatment and prevention of senescence-associated diseases or disorders such as cardiovascular diseases including atherosclerosis and heart failure, neurological diseases like Alzheimer's and Parkinson's, inflammatory diseases, metabolic disorders including type 2 diabetes, eye diseases including cataracts and glaucoma, dermatologic diseases, sarcopenia, fibroses, cancer, chemotherapeutic and radiotherapy side effects, and others as enumerated.
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