Substituted N-acetyl-L-cysteine derivatives and related compounds
Inventors
Neary, Michael • Nieman, James • Tanis, Steven • Lawton, Daniel • Smith, Garry
Assignees
Naeja Pharmaceutical Inc • Promentis Pharmaceuticals Inc • Fox Chase Chemical Diversity Center Inc
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Publication Number
US-9630937-B2
Publication Date
2017-04-25
Expiration Date
Abstract
Novel substituted N-acetyl-L-cysteine (NAC) derivatives and related compounds and methods of using these compounds 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 substituted N-acetyl-L-cysteine (NAC) derivative compounds defined by formulas I and II, where variable substituents R2, R3, and R4 are present on a thioester-containing scaffold. The scope includes preferred selections of substituents and example compounds including Pro-2022, Pro-2023, Pro-2024, Pro-3010, Pro-4006, Pro-4011, Pro-4047, Pro-4051, and Pro-4051a, among others.
The patent discloses synthetic procedures and related compounds including amino acid/cysteine-prodrug intermediates and further protected piperazine derivatives. The described intermediates and prodrugs include benzoylsulfanyl, benzyloxycarbonyl, esters, and amides, including compounds identified as N51, N53, Pro-4046/4047/4011/4051/4051a, and related prodrugs.
The substituted NAC derivative compounds are framed as therapeutics intended for Central Nervous System (CNS) disorders and related conditions. The document links the compounds to biochemical pathways involving oxidative stress, reactive oxygen species (ROS), glutathione levels, glutamate signaling, and cystine-glutamate antiporter/System xc− activity, and positions the compounds as agents that address oxidative imbalance and glutamatergic dysfunction through effects associated with glutathione and cystine-glutamate antiporter activity.
Claims Coverage
The independent claims cover compound/formula scope, salt or ester embodiments, pharmaceutical compositions with a pharmaceutically acceptable carrier, and methods of treatment for selected central nervous system (CNS) disorders or conditions. The stated mechanistic objectives include reducing oxidative stress, improving glutamate signaling, increasing glutathione levels, and improving cystine-glutamate antiporter activity.
Substituted N-acetyl-L-cysteine compound of formula
A compound of Formula I or II, wherein the variable substituents and thioester-containing scaffold define the substituted NAC derivative compounds.
Pharmaceutically acceptable salt or ester of a compound of formula
A pharmaceutically acceptable salt or ester of the compound of formula, encompassing salt and ester forms of the substituted NAC derivative compounds.
Substituted NAC derivative compound of formula
A compound of a specified formula, including CNS-focused therapeutic use and mechanistic outcomes as recited by dependent claims.
Pharmaceutically acceptable salt or ester of a compound of formula
A pharmaceutically acceptable salt or ester of the compound of formula, with dependent coverage for pharmaceutical compositions and specific CNS and mechanistic treatment outcomes.
Treating a selected central nervous system (CNS) disorder by administering a therapeutically effective amount
A method for treating a selected central nervous system (CNS) disorder or condition by administering a therapeutically effective amount of the compound to a subject who needs it.
Providing a pharmaceutical composition with a pharmaceutically acceptable carrier
A pharmaceutical composition that includes the compound together with a pharmaceutically acceptable carrier.
Reducing oxidative stress in a subject by administering a therapeutically effective amount
A method of reducing oxidative stress in a subject by administering a therapeutically effective amount of the compound.
Improving glutamate signaling in a subject by administering a therapeutically effective amount
A method for improving glutamate signaling in a subject by administering a therapeutically effective amount of the compound.
Increasing glutathione levels in a subject by administering a therapeutically effective amount
A method for increasing glutathione levels in a subject by administering a therapeutically effective amount of the compound.
Improving cystine-glutamate antiporter activity in a subject by administering a therapeutically effective amount
A method for improving cystine-glutamate antiporter activity in a subject by administering a therapeutically effective amount of the compound.
Overall, the claims coverage centers on substituted NAC derivative compounds and their pharmaceutically acceptable salt or ester forms, with dependent coverage tying administration to selected CNS disorders and mechanistic objectives involving oxidative stress, glutamate signaling, glutathione levels, and cystine-glutamate antiporter activity.
Stated Advantages
Reducing oxidative stress in a subject.
Improving glutamate signaling in a subject.
Increasing glutathione levels in a subject.
Improving cystine-glutamate antiporter activity in a subject.
Providing treatment of selected central nervous system (CNS) disorders or conditions.
Documented Applications
In vitro cellular assays using human astrocytoma (1321N1) and mixed cortical cells to evaluate effects on 14C-cystine uptake, 3H-glutamate release, and intracellular thiol/cysteine levels, concluding cysteine prodrug activity.
In vivo evaluation using prepulse inhibition (MK-801 schizophrenia model) and elevated plus maze to assess CNS penetration and antipsychotic-like effects.
Oral brain pharmacokinetics measuring brain NAC and glutathione using LC-MS/MS, with reported time- and dose-dependent increases.
Treating selected Central Nervous System (CNS) disorders and conditions including schizophrenia, drug craving and drug addiction, trichotillomania, Huntington's disease, adrenoleukodystrophy/X-linked adrenoleukodystrophy (ABCD1), Leigh syndrome, Alpers' disease, MELAS, HIV-associated neurocognitive disorder, and hypoxic-ischemic encephalopathy.
Treating inherited mitochondrial disease selected from Leigh syndrome, Alpers' disease, and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS).
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