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.

项目概要 重度抑郁症 (MDD) 是一种严重的、使人衰弱的、经常反复发作的疾病，具有严重的 终生风险和高昂的社会成本抑郁症患者经常表现出各种共病症状， 包括情绪低落、失去动力和/或体验快乐的能力下降 （快感缺乏），兴趣和精力丧失，伴有心理和植物性变化，例如睡眠 和/或食欲障碍、疲劳、内疚感和绝望感、难以保持精神集中，以及 反复出现的自杀念头常常与其他常见疾病同时发生，包括身体疾病。 目前可用的抗抑郁药物疗效有限，起效缓慢， 传统的抗抑郁药物通过血清素和药物发挥作用，并受到不良副作用的阻碍。 尽管通过谷氨酸能系统发挥作用的新药物显示出一些希望，但仍有一些前景。 已经确定了对改善中枢多巴胺能系统的大量未满足的需求。 作为替代目标，特别是通过多巴胺参与奖励、快感缺失和相关 事实上，一些临床研究表明直接和间接多巴胺激动剂对 MDD 有益。 作为多巴胺代谢的关键酶，儿茶酚-O-甲基转移酶（COMT）已成为多巴胺代谢的关键酶。 治疗各种中枢和周围神经系统疾病的有吸引力的目标，包括MDD， COMT 存在两种形式，一种是可溶性形式 (S-COMT)。 外周组织中存在，膜结合形式（MB-COMT）主要在大脑中表达。 临床上的抑制剂含有硝基儿茶酚部分，与脑渗透性差和毒性有关。 为了克服这些问题，Psy Therapeutics 正在开发一系列脑渗透小分子 基于缺乏硝基儿茶酚基团的新型支架的 COMT 抑制剂，该支架是使用 DNA 发现的 初步的结构活性关系（SAR）工作导致了 COMT 的识别。 抑制剂具有良好的微粒体稳定性、良好的脑渗透性和对S-COMT的有效抑制作用 MB_COMT 第一阶段申请的目标是进一步优化先导化合物以增强 针对 S- 和 MB-COMT 的效力以及体外药理学特征（目标 1），我们将在目标 2 中进行评估。 多巴胺代谢的药代动力学和生物标志物，以鉴定具有改善口服作用的 COMT 抑制剂 这些化合物在体内抑制 COMT 的生物利用度和脑渗透能力。 目标 3 中将使用触摸屏概率奖励任务 (PRT) 模型评估反应能力和学习能力 在小鼠中，以托卡朋作为对照，作为临床前模型，其结果与成功的人类研究非常相似。 该提案的完成将确定一种新型 COMT 抑制剂作为候选药物，以推进 IND 启用 研究作为抑郁症的潜在新疗法。