Potent and selective inhibitors of monoamine transporters; method of making; and use thereof
Inventors
Newman, Amy Hauck • Okunola-Bakare, Oluyomi M. • Cao, Jianjing
Assignees
US Department of Health and Human Services
Publication Number
US-10590074-B2
Publication Date
2020-03-17
Expiration Date
2034-03-07
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Abstract
Disclosed herein are bisarylmethylthioacetamides and bisarylmethylthioethylamines useful as inhibitors of monoamine transporters. The compounds are potent and/or selective inhibitors of dopamine (DA), serotonin (5-HT), and/or norepinephrine (NE) reuptake via their respective transporters, DAT, SERT and NET. Also disclosed are methods for eliciting a wake-promoting or cognitive or attention enhancing effect and for treating substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder or other neuropsychiatric disorders sleep disorders or cognitive impairment using the compounds.
Core Innovation
The invention disclosed relates to bisarylmethylthioacetamide and bisarylmethylthioethylamine compounds that function as inhibitors of monoamine transporters. These compounds are potent and/or selective inhibitors of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) reuptake via their respective transporters, DAT, SERT, and NET. The compounds show higher affinity for the monoamine transporters than modafinil and improved water solubility, potentially leading to lower effective doses and enhanced bioavailability in vivo.
The background identifies the problem with rapid reuptake of monoaminergic neurotransmitters being the terminal step in their synaptic signaling, mediated by DAT, SERT, and NET. Modafinil, an existing DA reuptake inhibitor, has a complex pharmacological profile, limited water solubility, and unclear mechanisms of clinical efficacy. There is a need for compounds with improved monoamine transporter affinities and better solubility properties to allow further investigation into novel mechanisms that may result in therapeutics without abuse liability.
To address these issues, the invention provides compounds of Formula I defined by specific aryl, heteroaryl, alkyl, and other substituents with particular provisos to ensure stability and desired properties. These compounds are formulated into pharmaceutical compositions and can be used in methods to elicit wake-promoting, cognition-enhancing, or mood-enhancing effects and to treat substance use disorders, attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder, sleep disorders, or cognitive impairment.
Claims Coverage
The patent includes one independent claim directed to a method of treatment using compounds of Formula V or their salts, with several dependent claims detailing specific substituents and configurations.
Method for treating substance use disorders with compounds of Formula V
A method comprising providing a therapeutically effective amount of a compound of Formula V or a pharmaceutically acceptable salt thereof to a patient in need, specifically for treating substance use disorders.
Specific substituent configurations of compounds of Formula V
The compounds used in the method have R5 selected from 3-phenylpropyl, —CH2CH(OH)CH3, or —CH2CH(OH)CH2Ph with X substituents located at para or meta positions chosen from fluoro, methyl, or CF3; Y is S or S(O); and Z is O or 2H.
Sulfoxide fragment stereochemistry
The compounds may have a sulfoxide fragment with either (R)-configuration or (S)-configuration, including racemic mixtures.
Pharmaceutical composition formulation
The compound or salt thereof may be formulated as a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier in forms such as injectable fluids, aerosols, creams, gels, tablets, pills, capsules, syrups, ophthalmic solutions, or transdermal patches.
The claims cover methods for treating substance use disorders by administering a compound of Formula V or its salt, with defined chemical substituents and stereochemistry, optionally formulated into suitable pharmaceutical compositions.
Stated Advantages
The compounds have higher affinity for monoamine transporters than modafinil, potentially enabling lower effective doses and better bioavailability in vivo.
Several compounds demonstrate improved water solubility compared to modafinil.
Certain compounds exhibit pronounced selectivity for the dopamine transporter (DAT) over serotonin (SERT) and norepinephrine transporters (NET).
Reduction of the amide carbonyl to amine substantially improves water solubility and binding affinities at all three monoamine transporters.
Compound 4g shows no locomotor stimulation up to 30 mg/kg in mice, unlike cocaine, indicating potential for treatment of stimulant abuse with reduced abuse liability.
Compound 4g exhibits metabolic stability in mouse plasma and reasonable metabolic stability in mouse liver microsomes, with reasonable pharmacokinetics including brain penetrability and bioavailability.
Documented Applications
Eliciting wake-promoting, cognition-enhancing, or mood-enhancing effects.
Treating substance use disorders including cocaine, methamphetamine, opioids, and nicotine abuse.
Treating attention deficit (hyperactivity) disorder (ADHD).
Treating depressive disorders and bipolar disorder.
Treating sleep disorders.
Treating cognitive impairment including impairment associated with psychostimulant abuse, schizophrenia, NeuroAIDS, Alzheimer's disease, cancer-associated fatigue, multiple sclerosis-associated fatigue, jet-lag, post-operative grogginess, age-related memory decline, obesity, anxiety, and obsessive-compulsive disorders.
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