Potent and selective inhibitors of monoamine transporters; method of making; and use thereof
Inventors
Newman, Amy Hauck • Okunola-Bakare, Oluyomi M. • Cao, Jianjing
Assignees
Usa REPRESENTED BY SECRETARY Dhhs AS • US Department of Health and Human Services
Publication Number
US-11555013-B2
Publication Date
2023-01-17
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 relates to bisarylmethylthioacetamides and bisarylmethylthioethylamines 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 are characterized by Formula I and its subgeneric formulas, incorporating variations in their chemical structure that influence binding affinity and selectivity. Pharmaceutical compositions comprising these compounds and methods for using them are also disclosed for therapeutic purposes.
The problem addressed by this invention arises from the need to develop effective monoamine transporter inhibitors with improved properties over existing compounds such as modafinil. Modafinil binds the dopamine transporter uniquely compared to cocaine and has limitations including non-aminergic structure and limited water solubility, complicating investigation and potentially reducing therapeutic efficacy. There is a need for compounds with enhanced transporter affinity, selectivity, and solubility to allow exploration of novel mechanisms for treating neuropsychiatric and other disorders while potentially reducing abuse liability.
Claims Coverage
The claims cover a method of treating attention deficit (hyperactivity) disorder using compounds of Formula V or their salts, with multiple inventive features related to the structural features and formulations of these compounds.
Use of compounds of Formula V for treating attention deficit hyperactivity disorder
The method involves providing a therapeutically effective amount of a compound of Formula V or salt thereof to a patient in need of treatment for attention deficit (hyperactivity) disorder.
Structural features of compounds effective in treatment
The compounds have substituent R5 selected from 3-phenylpropyl, —CH2CH(OH)CH3, or —CH2CH(OH)CH2Ph, with instances of X located at the para or meta position as fluoro, methyl, or CF3; Y is S or S(O); and Z is O or 2H.
Stereochemistry of sulfoxide fragment
The sulfoxide fragment in the compounds may have an (R)- or (S)-configuration.
Formulation as pharmaceutical composition
The compounds of Formula V or salts thereof are formulated as pharmaceutical compositions comprising at least one pharmaceutically acceptable carrier and may be formulated into injectable fluids, aerosols, creams, gels, tablets, pills, capsules, syrups, ophthalmic solutions, or transdermal patches.
The claims focus on methods of treatment for attention deficit (hyperactivity) disorder using specifically structured compounds of Formula V or their salts, emphasizing structural substituent characteristics, sulfoxide stereochemistry, and pharmaceutical formulation options.
Stated Advantages
The compounds have higher affinity for monoamine transporters compared to modafinil, potentially allowing lower effective doses and better bioavailability in vivo.
Several compounds exhibit improved water solubility over modafinil.
Some compounds show selectivity for dopamine transporter over serotonin and norepinephrine transporters, which may reduce side effects.
Certain compounds do not produce locomotor stimulation like cocaine, indicating potential reduced abuse liability.
Compound 4g demonstrates reasonable bioavailability and excellent blood-brain barrier penetration.
Documented Applications
Eliciting wake-promoting effects.
Enhancing cognition or attention.
Mood enhancement.
Treatment of substance use disorders including cocaine and methamphetamine abuse.
Treatment of attention deficit (hyperactivity) disorder (ADHD).
Treatment of depressive disorders, bipolar disorder, or other neuropsychiatric disorders.
Treatment of sleep disorders.
Treatment of cognitive impairment including cognitive impairment in psychostimulant abuse, schizophrenia, NeuroAIDS, Alzheimer's disease, depression, nicotine abuse, cancer-associated fatigue, multiple sclerosis-associated fatigue, jet-lag, post-operative grogginess, age-related memory decline, obesity, anxiety, or obsessive-compulsive disorders.
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