A New Approach for the Development of Novel Antipsychotic Drugs

 描述（由申请人提供）： 精神分裂症是一种脑部疾病，影响世界上约1%的人口，其中多达三分之一的患者是治疗抵抗性（TRS）。此外，精神分裂症与自杀意念有关，9-13%的患者最终结束了自己的生命。更令人不安的是，65%至80%的慢性精神分裂症门诊患者停止服用抗精神病药物，通常是因为缺乏疗效或无法忍受的不良反应。因此，迫切需要新的抗精神病药，以促进依从性并最终治疗疾病，包括治疗耐药性疾病。该提案的长期目标是开发新型小分子，其促进β-arrestin-2募集至D2 R，并同时与参与精神分裂症病理生理学的其他CNS受体相互作用，作为精神分裂症的新治疗选择。此外，所选择的化合物也不应与与现有药物的已知副作用相关的受体明显相互作用。我们已经确定了两种具有这种特征的先导化合物SYA 16263和SYA 16268，它们将成为实现这一长期目标的药物开发基础。为实现这一目标而提出的具体目标包括在精神病动物模型的一系列测试中评估SYA 16263（一种新发现的临床前候选药物），并证明没有不良事件，从而使我们能够将这种药物或相关类似物推向临床。由于其新的功能特性，我们还计划进行SYA 16263的结构功能选择性关系研究。Specific Aim 2将优化SYA 23013和SYA 29875这两种我们实验室新发现的药物与D2 R、5 HT 1AR和5 HT 7 R的结合亲和力，同时最大限度地减少5 HT 2BR、5 HT 2CR和H1 R的相互作用（Ki > 500 nM）。设计策略是获得促进b-抑制蛋白-2募集至D2 R并作为5 HT 1AR、5 HT 2AR和5 HT 7 R的拮抗剂（Ki<10 nM）的高效化合物。具体目标3涉及每年对具体目标1和2中获得的至少1种药物进行体外ADME和体内药理学评价，这些药物符合规定的理化特性，包括Lipinski五法则（Ro 5）、渗透性和代谢稳定性。最后，作为教师发展补助金，我们还提出了一个具体的目标4，其中涉及精心策划的教师发展战略，这将导致获得非SCORE赠款。这些活动包括与该领域的专家重新建立充满活力的合作关系， 研究助理/技术人员帮助PI实现提案目标，在FAMU建立化合物筛选实验室;每年撰写和发表≥2篇文章，每年至少撰写一份提案，包括向非SCORE资助机构提交的R21或RO 1提案，以及与合作者提交的≥2份联合RO 1提案。

 DESCRIPTION (provided by applicant): Schizophrenia is a brain disorder that affects about 1% of the world's population and out of this number, up to a third of patients are treatment-resistant (TRS). In addition, schizophrenia is associated with suicidal ideation and 9-13% of patients eventually take their own lives. Even more troubling is the fact that 65 to 80 % of outpatients with chronic schizophrenia discontinue their antipsychotic medications, often because of a lack of efficacy or intolerable adverse effects. There is therefore an urgent need for new antipsychotics that promote compliance and ultimately treat the disease including the treatment resistant illness. The long-term goal of this proposal is to develop novel small molecules that promote β-arrestin-2 recruitment to D2R and simultaneously interact at other CNS receptors involved in the pathophysiology of schizophrenia as new treatment options for schizophrenia. In addition, selected compounds should also not interact appreciably with receptors associated with the known side effects of current drugs. We have identified two lead compounds with this profile, SYA16263 and SYA16268 and they will form the basis of drug development to accomplish this long-term goal. The specific aims proposed to accomplish this goal, include evaluation of SYA 16263, a newly identified preclinical candidate, in a battery of tests in animal models of psychosis and to demonstrate a lack of adverse events enabling us then to move this drug or the related analog toward the clinic. Because of its newly characterized functional profile, we also plan to conduct a structure functional selectivity relationship study on SYA 16263. Specific Aim 2 will optimize the binding affinity of SYA 23013 and SYA 29875 two newly discovered agents in our labs, to D2R, 5HT1AR and 5HT7R while minimizing interactions at 5HT2BR, 5HT2CR and H1R (Ki > 500 nM). The design strategy is to obtain high potency compounds that promote b-arrestin-2 recruitment to D2R and function as antagonists (Ki<10 nM) at 5HT1AR, 5HT2AR and 5HT7R. Specific Aim 3 involves performing in vitro ADME and in vivo pharmacological evaluations of at least 1 agent per year obtained in specific aims 1 and 2 that satisfy stated physicochemical characteristics, including Lipinski's rule of five (Ro5), permeability and metabolic stability. Finally, as a faculty development grant, we also propose a specific Aim 4 which involves orchestrating a Faculty Development Strategy that will lead to obtaining non-SCORE grants. The activities include re-establishing a vibrant collaboration with experts in the field and hiring research associates/technicians to help PI deliver on the proposal aims, to establish a compound screening lab in FAMU; to write and publish ≥2 articles per year and to write at least one proposal including an R21 or RO1 per year to non-SCORE funding agencies and ≥2 joint RO1 proposals with collaborators.