Ethyl (2R)-2-acetamido-3-(4-methylbenzoylsulfanyl)propanoate and uses thereof
Inventors
Neary, Michael • Nieman, James • Tanis, Steven • Lawton, Daniel
Assignees
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Publication Number
US-9012674-B1
Publication Date
2015-04-21
Expiration Date
Abstract
A novel substituted N-acetyl-L-cysteine (NAC) derivative and methods of using this compound for the treatment of diseases and/or conditions, including but not limited to diseases and/or conditions of, or involving, the Central Nervous System (CNS), including schizophrenia adrenoleukodystrophy, mitochondrial diseases (e.g. Leigh syndrome, Alpers' disease, and MELAS), Huntington's disease, trichotillomania, HIV-associated neurocognitive disorder, hypoxic-ischemic encephalopathy, drug craving, and drug addiction.
Core Innovation
The invention relates to a substituted N-acetyl-L-cysteine derivative, ethyl (2R)-2-acetamido-3-(4-methylbenzoylsulfanyl)propanoate (Pro-4051, Formula I), or a pharmaceutically acceptable salt thereof. The specification positions this compound as a cysteine prodrug intended for Central Nervous System (CNS) targeting and contrasts Pro-4051 with NAC, emphasizing differences in first-pass metabolism and CNS availability.
The problem addressed is associated with oxidative stress and glutamate-cystine antiporter (System x_c−) dysfunction, which is linked to CNS disorders such as schizophrenia. The therapeutic concept centers on restoring or supporting cysteine availability and related glutathione processes relevant to reactive oxidative species (ROS), glutamate signaling, and glutamate-cystine transport.
The specification further describes therapeutic areas connected to oxidative stress and ROS, including schizophrenia and additional CNS disorders. It also includes disease-context examples such as adrenoleukodystrophy (ABCD1) involving very-long chain fatty acids, mitochondrial diseases (Leigh syndrome, Alpers’ disease, MELAS), Huntington’s disease, HIV-associated neurocognitive disorder, and hypoxic-ischemic encephalopathy, with pharmaceutically acceptable salt/ester/prodrug forms and oral administration for CNS targeting.
Claims Coverage
The independent claim family centers on a compound defined by Formula I, including pharmaceutically acceptable salt or ester, with three inventive features across the claim set.
Compound of Formula I
A compound of formula I, or a pharmaceutically acceptable salt or ester thereof.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
Treating schizophrenia by administering therapeutically effective amount
A method for treating schizophrenia by administering a therapeutically effective amount of the compound of claim 1 to a subject in need.
Overall, the claim coverage is anchored in Pro-4051 (Formula I) and its pharmaceutically acceptable salt or ester, then extends to a pharmaceutical composition and a schizophrenia-specific therapeutic method via administration of a therapeutically effective amount.
Stated Advantages
Reduced first-pass metabolism compared with NAC, supporting improved CNS availability.
Inhibition of 14C-cystine uptake and increased 3H-glutamate release, consistent with modulation of glutamate-cystine antiporter-related processes.
Increased intracellular cysteine levels.
Improvement of MK-801-induced schizophrenia-like prepulse inhibition deficits.
Improved anxiety-related behavior in the elevated plus maze (open-arm time).
Elevates brain NAC levels after oral dosing and is associated with glutathione elevation at later timepoints.
Documented Applications
Therapeutic use in treating schizophrenia via CNS targeting using oral administration.
Therapeutic areas described as linked to oxidative stress/ROS and glutamate-cystine antiporter (System x_c−) dysfunction, including adrenoleukodystrophy (ABCD1), mitochondrial diseases (Leigh syndrome, Alpers’ disease, MELAS), Huntington’s disease, HIV-associated neurocognitive disorder, and hypoxic-ischemic encephalopathy.
Use of experimental models/assays described in the document, including MK-801 model for schizophrenia-like prepulse inhibition deficits and elevated plus maze for anxiety-related phenotype.
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