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; 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.

项目摘要 重度抑郁症（MDD）是一种严重的，令人衰弱的且经常发生的障碍 终身风险和高昂的社会成本。抑郁症患者经常表现出多种合并症状， 包括情绪低落，动力丧失和/或降低体验乐趣的能力 （Anhedonia），失去利益和能量，再加上心理和营养变化，例如睡眠 和/或食欲灾难，疲劳，内gui和绝望的感觉，保持精神焦点的困难以及 自杀的反复思想。 MDD通常与其他常见疾病一起出现，包括两者 和精神疾病。目前可用的抗抑郁药显示出有限的效率，动作发作缓慢， 并受到不必要的副作用的阻碍。传统抗抑郁药通过血清素能和 去甲肾上腺素能系统。尽管通过谷氨酸能系统起作用的新药物表现出一定的希望，但 对改进药物的需求仍然很大。已经确定了中央多巴胺能系统 作为替代目标，尤其是通过多巴胺参与奖励，Anhedonia及相关目标 功能。实际上，一些临床研究表明，MDD中的直接和间接多巴胺激动剂有益。 作为多巴胺代谢中的关键酶，儿茶醇-O-甲基转移酶（COMT）已成为一种 治疗各种中枢和周围神经系统疾病（包括MDD）的有吸引力的目标 帕金森氏病和其他与多巴胺有关的疾病。存在两种形式的COMT，一种实体形式（S-COMT） 在周围组织和膜结合形式（MB-COMT）中，主要在大脑中表达。当前comt 诊所中的抑制剂包含一个与脑穿透性和毒性不佳有关的硝化甲醇部分。 为了克服这些问题，PSY Therapeutics正在开发一系列脑部渗透剂小分子 基于缺乏使用DNA发现的氮气蛋白酶组的新型脚手架的COMT抑制剂 编码的库屏幕。初步结构活动关系（SAR）努力导致COMT识别 具有良好微粒体稳定性，良好脑穿透性良好以及潜在抑制S-COMT和的抑制剂 mb_comt。 I阶段I应用的目的是采取进一步的优化努力以增强 针对S-和MB-COMT以及体外药物剖面的效力（AIM 1）。在AIM 2中，我们将评估 多巴胺代谢的药代动力学和生物标志物，以鉴定口服改善的COMT抑制剂 生物利用度和脑穿透性抑制体内COMT。这些化合物调节奖励的能力 响应和学习将在AIM 3中使用触摸屏概率奖励任务（PRT）模型评估 在小鼠中，以托尔卡酮作为对照，作为临床前模型，其结果与人类研究非常相似。成功的 该提案的完成将确定一种新颖的COMT抑制剂作为一种候选药物，以提高IND启用 研究是一种潜在的抑郁症治疗方法。