Quinone reductase 2 inhibitor compounds and uses thereof
Inventors
Lascola, Christopher D. • Laskowitz, Daniel T.
Assignees
Publication Number
US-12331032-B2
Publication Date
2025-06-17
Expiration Date
2039-10-16
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Abstract
Provided herein according to some embodiments is a compound of Formula (I): [Formula], or a pharmaceutically acceptable salt or prodrug thereof. Compositions comprising the compound, and uses thereof for inhibiting the activity of quinone reductase-2, as well as in methods of treatment, are also provided.
Core Innovation
The invention provides a new class of compounds of Formula (I), or pharmaceutically acceptable salts or prodrugs thereof, that act as inhibitors of quinone reductase 2 (QR2). These compounds feature a nitrogen-containing heterocyclo or nitrogen-containing heteroaryl as R1, with optional substitutions including fluoromethyl, difluoromethyl, or trifluoromethyl groups. The compounds and compositions comprising them are designed specifically to inhibit the activity of QR2 and are intended for use in various methods of treatment.
The problem addressed stems from clinical limitations of traditional QR2 inhibitors like chloroquine and hydroxychloroquine, which are known to accumulate in lysosomes and cause significant retinal and cardiac toxicities. This lysosomal trapping leads to important side effects that limit therapeutic efficacy and long-term use. The invention seeks to overcome these toxicity issues by providing QR2 inhibitors with reduced lysosomal accumulation, as demonstrated by maintaining a positive log D value at lysosomal pH, to enhance safety while preserving therapeutic benefits.
The compounds disclosed exhibit strong membrane permeability at lysosomal pH, thereby reducing organelle trapping and associated toxicity. They are shown, through detailed synthesis and comparative data, to be potent QR2 inhibitors with potential for treatment across a range of conditions, including infectious and autoimmune diseases, acute neural injury, chronic neurological disorders, and diseases associated with mitochondrial dysfunction.
Claims Coverage
There are multiple inventive features described in the independent claims, primarily relating to novel compounds of Formula (I), methods of use, compositions, and their superior physicochemical and pharmacological properties.
Compound of Formula (I)
A compound of Formula (I) where R1 is a nitrogen-containing heterocyclo or a nitrogen-containing heteroaryl, and the compound may be optionally substituted one, two, or three times with fluoromethyl, difluoromethyl, or trifluoromethyl, or is a pharmaceutically acceptable salt or prodrug.
Compound with positive log D at lysosomal pH
The compound as described in claim 1, wherein the compound has a positive log D value at approximately pH 4 to pH 5, indicating retained membrane permeability and reduced lysosomal accumulation.
Composition comprising the compound and carrier
A composition including the compound of claim 1 and a carrier, wherein the carrier may be a pharmaceutically acceptable carrier.
Method for inhibiting quinone reductase 2 activity
A method comprising contacting QR2 with the compound of claim 2, either in vitro or in vivo, resulting in inhibition of QR2 activity.
Treatment of malaria using the compound
A method of treatment for malaria in a subject in need thereof, comprising administering a treatment-effective amount of the compound of claim 1.
Treatment of immune disorder using the compound
A method of treatment for an immune disorder in a subject in need thereof, comprising administering a treatment-effective amount of the compound of claim 1.
Treatment of lupus using the compound
A method of treatment for lupus in a subject in need thereof, comprising administering a treatment-effective amount of the compound of claim 1.
Treatment of disorders associated with mitochondrial dysfunction
A method of treatment for a disorder associated with mitochondrial dysfunction in a subject in need thereof, comprising administering a treatment-effective amount of the compound of claim 1.
The inventive features center on novel QR2 inhibitor compounds, improved physicochemical characteristics reducing lysosomal accumulation, pharmaceutical compositions, and broad methods of use for treating QR2-related diseases.
Stated Advantages
Provides QR2 inhibitory properties with reduced lysosomal accumulation, thereby minimizing toxicity such as retinal and cardiac toxicity seen with traditional QR2 inhibitors like chloroquine.
Compounds maintain membrane permeability at lysosomal pH (positive log D at pH 4–5), reducing organelle trapping and improving safety profile.
Demonstrates durable and improved neuroprotective effects and therapeutic efficacy compared to existing QR2 inhibitors in models of acute neural injury.
Does not show potent hERG ion channel inhibition, mutagenicity, or poor membrane permeability, indicating favorable drug-like properties.
Documented Applications
Treatment of malaria in subjects in need thereof.
Treatment of immune disorders, including but not limited to lupus.
Treatment of lupus, including systemic lupus erythematosus and lupus nephritis.
Treatment of disorders associated with mitochondrial dysfunction, such as neurodegenerative diseases (Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS, Friedrich's ataxia), cardiovascular diseases, diabetes, autoimmune diseases, psychiatric diseases, gastrointestinal disorders, fatiguing disorders, musculoskeletal diseases, cancer, and chronic infections.
Treatment of acute neural injury (traumatic brain injury, stroke, hypoxic/ischemic brain injury).
Treatment of chronic neurological disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, secondary dementias, movement disorders, epilepsy, and CNS lupus.
Treatment of infectious diseases including parasitic, bacterial, and viral infections (malaria, amebiasis, Lyme disease, HIV, ebola, chikungunya, dengue, Zika).
Treatment of cancer, including radiosensitization and chemosensitization.
Treatment of subjects at increased risk for cerebrovascular disease.
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