Development of brain-penetrant COMT inhibitors for the treatment of depressive disorders

开发用于治疗抑郁症的脑渗透性 COMT 抑制剂

• 批准号: 10696272
• 负责人: Alan J. Cross
• 金额: $ 45.84万
• 依托单位: PSY THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10696272
• 关键词: Affect; Anhedonia; Antidepressive Agents; Arginine; Behavioral; Binding; Biological Availability; Biological Markers; Blood; Brain; Catechols; Central Nervous System; Central Nervous System Agents; Central Nervous System Diseases; Cerebrospinal Fluid; Clinic; Clinical Research; DNA; Depressed mood; Depressive disorder; Desire for food; Development; Disease; Docking; Dopamine; Dopamine Agonists; Dose; Drug Kinetics; Enzymes; Family; Fatigue; Feeling; Feeling suicidal; Future; Glutamates; Goals; Guilt; Hamilton Rating Scale for Depression; Heterogeneity; Human; In Vitro; Intravenous; Learning; Libraries; Major Depressive Disorder; Measures; Medicine; Membrane; Mental Depression; Mental disorders; Metabolic; Metabolism; Microsomes; Modeling; Moods; Motivation; Mus; Oral; Outcome; Parkinson Disease; Patients; Penetration; Peripheral; Peripheral Nervous System Diseases; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Phenotype; Pre-Clinical Model; Property; Proteins; Psyche structure; Recombinants; Recurrence; Rewards; Roentgen Rays; Series; Sleep; Small Business Innovation Research Grant; Structure; Structure-Activity Relationship; System; Therapeutic; Tissues; Toxic effect; Transferase; alternative treatment; analog; associated symptom; counterscreen; depressed patient; depressive symptoms; dopamine system; drug action; drug candidate; drug metabolism; efficacy evaluation; efficacy testing; experience; improved; in silico; in vivo; inhibitor; interest; intraperitoneal; lead candidate; lead optimization; lifetime risk; male; mouse model; nanomolar; neuropsychiatric disorder; neuropsychiatry; noradrenergic; novel; novel therapeutics; pharmacologic; pleasure; psychologic; response; scaffold; side effect; small molecule; small molecule inhibitor; societal costs; tolcapone; touchscreen; translational model

PROJECT SUMMARY Major depressive disorder (MDD) is a serious, debilitating, and often recurring disorder with a substantial lifetime risk and a high societal cost. Depressed patients frequently display a variety of co-morbid symptoms, including depressed moods, loss of motivation and/or reductions in the ability to experience pleasure (anhedonia), loss of interest and energy, combined with psychological and vegetative changes such as sleep and/or appetite disturbances, fatigue, feelings of guilt and despair, difficulties in maintaining mental focus, and recurrent thoughts of suicide. MDD often occurs together with other common illnesses, including both physical and psychiatric disorders. Currently available antidepressant drugs display limited efficacy, slow onset of action, and are hampered by unwanted side effects. Traditional antidepressant drugs act through serotonergic and noradrenergic systems. Although newer drugs acting through glutamatergic systems show some promise, there remains considerable unmet need for improved medications. Central dopaminergic systems have been identified as an alternative target, particularly through the involvement of dopamine in reward, anhedonia, and related functions. Indeed, several clinical studies demonstrate benefit with direct and indirect dopamine agonists in MDD. As a key enzyme in dopamine metabolism, catechol-O-methyl transferase (COMT) has emerged as an attractive target for the treatment of various central and peripheral nervous systems disorders, including MDD, Parkinson’s disease, and other dopamine-related disorders. Two forms of COMT exist, a soluble form (S-COMT) in peripheral tissues, and a membrane-bound form (MB-COMT), mainly expressed in the brain. Current COMT inhibitors in the clinic contain a nitrocatechol moiety that is associated with poor brain penetration and toxicity. To overcome these problems, Psy Therapeutics is developing a series of brain-penetrant small molecule inhibitors of COMT based on novel scaffolds lacking a nitrocatechol group that were discovered using a DNA encoded library screen. Preliminary structure activity relationship (SAR) efforts led to the identification of COMT inhibitors with good microsomal stability, good brain penetration, and potent inhibition of S-COMT and MB_COMT. The goal of this Phase I application is to pursue further lead optimization efforts to enhance the potency against both S- and MB-COMT and in vitro pharmacological profile (aim 1). In aim 2 we will evaluate pharmacokinetics and biomarkers of dopamine metabolism to identify COMT inhibitors with improved oral bioavailability and brain penetration that inhibit COMT in vivo. The ability of these compounds to modulate reward responsivity and learning will be assessed in aim 3 using a touchscreen Probabilistic Reward Task (PRT) model in mice, with tolcapone as control, as a preclinical model with outcomes very similar to human studies. Successful completion of this proposal will identify a novel COMT inhibitor as a candidate drug to advance to IND enabling studies as a potential new treatment for depression.

项目总结