DAAO Inhibitors for the treatment of Schizophrenia

描述(申请人提供)：累积证据表明，通过甘氨酸调节部位的NMDA受体的变构激活为精神分裂症的治疗提供了新的治疗潜力。D-丝氨酸是甘氨酸调节部位的一种内源性激动剂，临床研究表明它对治疗精神分裂症的阳性、阴性和认知症状有效。尽管临床数据非常令人鼓舞，但D-丝氨酸的临床开发可能会面临障碍，因为疗效所需的高剂量(大约每天2克)。这主要是由于外周给药的D-丝氨酸通过D-氨基酸氧化酶(DAAO)进行大量代谢，D-氨基酸氧化酶是一种在肝脏、肾脏和脑中表达的黄素酶。DAAO介导的D-丝氨酸代谢不仅限制了D-丝氨酸的生物利用度，而且可能通过产生过氧化氢来诱导肾脏毒性。因此，我们假设阻断DAAO介导的D-丝氨酸代谢可以显著降低疗效所需的剂量，同时防止过氧化氢引起的外周毒性。为此，我们发现，在精神分裂症的动物模型中，D-丝氨酸和DAAO抑制剂联合应用显著增加了血浆和大脑中D-丝氨酸的水平，并增强了D-丝氨酸的体内效力。拟议研究的目标是通过实施一项战略研究计划将我们的发现转化为创新的治疗方法，该战略研究计划包括：(目标1)对苯并异恶唑衍生物和其他类别的稠合双环化合物进行先导优化研究，以建立构效关系(结构-活性关系)，并确定有效的、选择性的、无毒的和代谢稳定的类药物DAAO抑制剂；(目的2)评估目标1中确定的有效的类药物DAAO抑制剂对D-丝氨酸口服生物利用度的影响；(目的3)评估目标2中确定的DAAO抑制剂对D-丝氨酸减弱苯环利定(PCP)诱导的小鼠脉冲前抑制(PPI)缺陷的能力的影响；(目标4)评估目标3中确定的DAAO抑制剂对D-丝氨酸减轻精神分裂症遗传小鼠模型中PPI缺陷的能力的影响。在这个项目完成后，我们希望找到临床前候选DAAO抑制剂，可能导致一种真正新颖的抗精神病药物用于精神分裂症的治疗。

DESCRIPTION (provided by applicant): Cumulative evidence suggests that allosteric activation of the NMDA receptor through the glycine modulatory site provides new therapeutic potential for the treatment of schizophrenia. D-Serine, an endogenous agonist at the glycine modulatory site, has been shown to be effective at treating positive, negative, and cognitive symptoms of schizophrenia in clinical studies. Despite the highly encouraging clinical data, clinical development of D-serine will likely face obstacles because of the high dosages required for efficacy (approximately 2 grams per day). This is primarily due to the substantial metabolism of peripherally administered D-serine by D-amino acid oxidase (DAAO), a flavoenzyme expressed in the liver, kidneys, and brain. DAAO-mediated metabolism of D-serine not only limits D-serine bioavailability but also has the potential to induce kidney toxicity through the generation of hydrogen peroxide. Therefore, we hypothesize that blockade of DAAO-mediated D-serine metabolism could substantially lower the dosages required for efficacy while preventing hydrogen peroxide-induced peripheral toxicity. To this end, we found that co-administration of D-serine and a DAAO inhibitor significantly increases plasma and brain levels of D-serine and enhances in vivo potency of D-serine in an animal model of schizophrenia. The goal of the proposed research is to translate our findings into innovative therapeutics by conducting a strategic research plan that consists of the following: (Aim 1) Perform lead optimization studies on benzoisoxazole derivatives and other classes of fused bicyclic compounds to establish SAR (structure-activity relationships) and identify potent, selective, non-toxic, and metabolically stable drug-like DAAO inhibitors; (Aim 2) Assess the effects on D-serine oral bioavailability of potent drug-like DAAO inhibitors identified in Aim 1; (Aim 3) Assess the effect of DAAO inhibitors identified in Aim 2 on D-serine's ability to attenuate phencyclidine (PCP) induced prepulse inhibition (PPI) deficits in mice; (Aim 4) Assess the effects of DAAO inhibitors identified in Aim 3 on D-serine's ability to attenuate PPI deficits in a genetic mouse model of schizophrenia. Upon completion of this project, we expect to identify preclinical candidate DAAO inhibitors that could lead to a truly novel antipsychotic drug for the treatment of schizophrenia.