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

项目总结 重度抑郁障碍(MDD)是一种严重的、使人衰弱的、经常反复发作的疾病，具有显著的 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)，兴趣和精力的丧失，结合心理和植物人的变化，如睡眠 和/或食欲障碍，疲倦，内疚和绝望，难以保持精神集中，以及 反复出现的自杀念头。MDD通常与其他常见疾病一起发生，包括 和精神障碍。目前可用的抗抑郁药物显示出疗效有限，起效慢， 并受到不想要的副作用的阻碍。传统的抗抑郁药物通过5-羟色胺能和 去甲肾上腺素能系统。尽管通过谷氨酸能系统作用的新药显示出一些希望，但 对改进药物的需求仍有相当大的未得到满足。中枢多巴胺能系统已被识别 作为一种替代靶点，特别是通过多巴胺参与奖赏、快感缺失和相关的 功能。事实上，几项临床研究表明，直接和间接的多巴胺激动剂对MDD有好处。 儿茶酚-O-甲基转移酶(COMT)是多巴胺代谢过程中的一个关键酶。 治疗各种中枢和周围神经系统疾病的有吸引力的靶点，包括MDD， 帕金森氏症和其他与多巴胺相关的疾病。COMT存在两种形式，一种是可溶性形式(S-COMT) 在外周组织中，以及一种膜结合型(MB-COMT)，主要在大脑中表达。当前COMT 临床上的抑制剂含有一种与脑渗透性差和毒性有关的硝基儿茶酚部分。 为了克服这些问题，PSY治疗公司正在开发一系列脑穿透小分子 基于利用DNA发现的新型支架材料的COMT抑制剂 编码库屏幕。初步结构活性关系(SAR)的努力导致了COMT的鉴定 具有良好的微球稳定性、良好的脑渗透性和对S-羟色胺和黄曲霉毒素的有效抑制作用 MB_COMT。此第一阶段应用程序的目标是进一步进行领先的优化工作，以增强 对S和MB-COMT的效力和体外药理学特征(目标1)。在目标2中，我们将评估 改良口服COMT抑制剂的药代动力学和多巴胺代谢生物标志物研究 体内抑制COMT的生物利用度和脑渗透。这些化合物调节奖赏的能力 在目标3中，将使用触摸屏概率奖励任务(PRT)模型评估响应性和学习能力 在小鼠身上，以Tolcapone为对照，作为临床前模型，结果与人类研究非常相似。成功 这项提案的完成将确定一种新的COMT抑制剂作为候选药物，以促进IND的实现 作为一种潜在的抑郁症新疗法的研究。

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.