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-10913711-B2
Publication Date
2021-02-09
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 act as inhibitors of monoamine transporters. These compounds are potent and/or selective in inhibiting the reuptake of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) through their respective transporters, DAT, SERT, and NET.
The background highlights the rapid reuptake of the monoaminergic neurotransmitters dopamine, serotonin, and norepinephrine as a terminal step in their synaptic signaling. Drugs like cocaine and methamphetamine exert their effects by inhibiting DA reuptake. Modafinil, an existing compound, also inhibits DA reuptake but has limitations including being non-aminergic with limited water solubility, hampering in vitro and in vivo investigations due to the high concentrations needed. Modafinil’s unique binding at DAT and pharmacological profile suggest therapeutic potential with less abuse liability, but there remains uncertainty regarding its clinical efficacy related to other interaction targets.
The problem being addressed is the need for compounds with improved monoamine transporter affinity and enhanced solubility over modafinil to allow better investigation and therapeutic benefit. The invention provides compounds of Formula I with higher affinity for the monoamine transporters, potentially allowing lower doses and better bioavailability, as well as improved water solubility compared to modafinil.
Claims Coverage
The claims focus on methods for eliciting a wake-promoting effect using compounds of Formula V or their salts, specifying various substituents and configurations. There are 17 claims with inventive features related to compound structure, stereochemistry, substitution patterns, and pharmaceutical formulation.
Use of compounds of Formula V for wake-promoting effect
A method for eliciting a wake-promoting effect comprising providing a therapeutically effective amount of a compound of Formula V or its salt to a patient in need.
Specific substituents and configurations of the compound
Compounds where R5 is 3-phenylpropyl, —CH2CH(OH)CH3, or —CH2CH(OH)CH2Ph; X substituents at para or meta positions as fluoro, methyl, or CF3; Y is S or sulfoxide S(O); and Z is O or 2H.
Stereochemical configuration of sulfoxide fragment
The method applies to compounds where the sulfoxide fragment has either the (R)- or (S)-configuration, including racemic mixtures.
Formulation as pharmaceutical compositions
The compounds or their salts may be formulated with pharmaceutically acceptable carriers in various dosage forms including injectable fluids, aerosols, creams, gels, tablets, pills, capsules, syrups, ophthalmic solutions, or transdermal patches.
The independent claims cover therapeutic methods employing compounds of Formula V or salts thereof with defined substituents and stereochemistry for wake-promotion, including pharmaceutical compositions and various formulations.
Stated Advantages
Higher affinity for monoamine transporters compared to modafinil, potentially allowing lower effective doses and better bioavailability in vivo.
Improved water solubility over modafinil.
Potential for therapeutic benefit over currently used monoamine transport inhibitors due to unique binding modes and selectivity.
Lack of locomotor stimulation effects up to 30 mg/kg demonstrated in animal models suggesting potential for treatment of substance abuse with less stimulant side effects.
Good metabolic stability in plasma and reasonable metabolic profile in liver microsomes.
Excellent brain penetrability and reasonable bioavailability demonstrated in pharmacokinetic studies in mice.
Documented Applications
Eliciting wake-promoting, cognition-enhancing, or mood-enhancing effects.
Treatment of substance use disorders, including cocaine and methamphetamine abuse.
Treatment of attention deficit (hyperactivity) disorder, depressive disorders, bipolar disorder, sleep disorders, cognitive impairment including in psychostimulant abuse, schizophrenia, and NeuroAIDS.
Treatment of Alzheimer’s disease, nicotine abuse (e.g., smoking cessation), cancer-associated and multiple sclerosis-associated fatigue, jet-lag, post-operative grogginess, age-related memory decline, obesity, anxiety, and obsessive-compulsive disorders.
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