Deuterated Alpha5 subunit-selective negative allosteric modulators of gamma-aminobutyric acid type a receptors as fast acting treatment for depression and mood disorders
Inventors
Thompson, Scott • Van Dyke, Adam • Thomas, Craig • Morris, Patrick
Assignees
University of Maryland Baltimore • US Department of Health and Human Services
Publication Number
US-11897875-B2
Publication Date
2024-02-13
Expiration Date
2038-08-28
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Abstract
The present invention relates to novel alpha5 subunit-selective negative allosteric modulators of GABAA receptors that have been deuterated to improve their medicinal properties by prolonging their half-lives, rendering them useful as fast-acting pharmaceutical treatments for depression related disorders.
Core Innovation
The invention relates to novel alpha5 subunit-selective negative allosteric modulators (NAMs) of GABAA receptors that have been deuterated to improve their medicinal properties by prolonging their half-lives. These deuterated compounds are useful as fast-acting pharmaceutical treatments for depression-related disorders and various psychiatric and neurological conditions. The deuterium substitution specifically targets positions in the molecules that are substrates for hydrolysis by liver enzymes to slow metabolism and extend bioavailability.
The problem addressed by the invention is that current alpha5 subunit-selective GABAA receptor NAMs have pharmacokinetic profiles that limit their clinical utility, due to rapid hydrolysis and short biological half-life. Existing antidepressant therapies, such as SSRIs, require prolonged treatment periods and have limited efficacy, while current fast-acting antidepressants under development have side effects that restrict use. Therefore, there is a need for novel compounds that act rapidly with improved pharmacokinetics and fewer side effects for treating depression and related disorders.
Claims Coverage
The patent includes one independent claim focusing on methods of treating depression-related disorders using specific deuterated GABAA5-NAM compounds. The inventive features center on the compound structures, administration methods, dosage regimens, and combination therapies.
Use of deuterated GABAA5-NAM compounds for treating depression-related disorders
A method of treating depression-related disorders in human subjects by administering a therapeutically effective amount of a deuterated GABAA5 negative allosteric modulator compound of Formula I or Formula II.
Administration routes and dosing schedules
The deuterated compounds are administered via various routes including oral, intradermal, intramuscular, intraperitoneal, intravenous, insufflation, or dermal patch. Dosing can occur every 0.5 to 4 days, allowing for improved treatment regimens.
Combination therapy with additional antidepressants
The method includes administering the deuterated GABAA5-NAM compound in combination with other antidepressant drugs such as monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, triple reuptake inhibitors, CNS acetylcholine modulators, stimulants, anti-glucocorticoids, NMDA receptor antagonists, tricyclic antidepressants, or combinations thereof.
Specific targeted depression-related disorders and compound selections
The depression-related disorders treated include a wide range of conditions such as major depressive disorder, dysthymia, suicidality, bipolar depression, psychotic depression, atypical depression, seasonal affective disorder, post-traumatic stress disorder, postpartum depression, treatment-resistant depression, and those secondary to conditions like tumors or substance abuse. The compounds used include deuterated versions of (3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4yl)methanol, 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4yl-methoxy)nicotinonitrile, 6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)nicotinic acid, and (1,1-dioxidothiomorpholino)(6-((3-(4-fluorophenyl)-5-(methyl-d3)isoxazol-4-yl)methoxy)pyridine-3-yl)methadone.
The independent claim covers methods of treating depression-related disorders using deuterated alpha5 subunit-selective GABAA NAM compounds with specified chemical structures, administration routes, dosing frequencies, use in combination with other antidepressants, and targeting a broad spectrum of depressive and related disorders. The inventive features focus on the improved pharmacokinetic properties achieved through deuteration and their therapeutic utility.
Stated Advantages
Deuteration prolongs the biological half-life of the alpha5-selective GABAA NAM compounds, improving metabolic stability and bioavailability.
Prolonged half-life reduces the need for frequent dosing, potentially lowering side effects and improving patient compliance.
The compounds provide a rapid antidepressant effect comparable to ketamine but without ketamine's side effects.
The selective targeting of alpha5 subunit-containing GABAA receptors addresses depression and related disorders more effectively than current fast-acting antidepressants.
Documented Applications
Treatment of depression-related disorders including major depressive disorder, dysthymia, suicidality, bipolar depression, psychotic depression, atypical depression, seasonal affective disorder, premenstrual dysphoric disorder, endogenous depression, catatonic depression, post-traumatic stress disorder, postpartum depression, and treatment-resistant depression.
Treatment of depression symptoms arising secondary to other medical conditions such as tumors, trauma, substance abuse disorder, and alcoholism.
Use as fast-acting pharmaceutical treatments for various psychiatric and neurological conditions including anxiety-related disorders, attention-related disorders, psychosis-related disorders, personality disorders, eating disorders, cognitive impairment, neuropathic pain, chronic muscle or bone pain, diabetic neuropathy, muscular weakness, recurring sleep episodes, migraine, addiction, and alcoholism.
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