NMDA receptor NR2D subtype-selective allosteric modulator for the treatment of im

NMDA 受体 NR2D 亚型选择性变构调节剂用于治疗 IM

基本信息

批准号：
8714057
负责人：
yuelian xu
金额：
$ 34.68万
依托单位：
CHINGLU PHARMACEUTICAL RESEARCH, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-05 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8714057
关键词：
ABCB1 gene Address Adult Adverse effects Agonist Animal Model Area Attention deficit hyperactivity disorder Back Behavior Therapy Brain Brain Part Brain region Budgets Cell Line Chemosensitization Child Development Disease Dopamine Dose Drug Kinetics Funding Glutamate Receptor Glutamates Goals Half-Life Hydrogen Bonding Impulsive Behavior Impulsivity In Vitro Industry Lead MDCK cell Medical Modeling Motor Activity N-Methyl-D-Aspartate Receptors N-Methylaspartate NR2D NMDA receptor National Institute of Mental Health Neurons Neurosciences Patients Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Phase Plasma Play Preclinical Drug Evaluation Prevalence Property Protein Binding Rat-1 Rattus Reaction Time Receptor Activation Reporting Series Small Business Innovation Research Grant Structure of subthalamic nucleus Surface Symptoms Synapses Synaptic Transmission Testing Therapeutic Work clinically significant drug candidate drug development drug discovery efficacy testing experience improved in vitro Assay in vivo meetings member novel strategies pre-clinical predictive modeling premature programs public health relevance receptor small molecule subcutaneous targeted delivery

项目摘要

DESCRIPTION (provided by applicant): This is an SBIR Phase I proposal is to test the feasibility of developing drug-like small molecules that are positive allosteric modulators of the NR2D subtype of the NMDA receptor (NR2D PAMs) for the purpose of treating impulsivity disorders, notably ADHD. The prevalence of ADHD in both children and adults is estimated at 4-5%. This disorder is treated with behavioral therapy and/or drugs; however, about 80% of patients continue to present with an unmet medical need. To address this need, we are developing NR2D PAMs. The subthalamic nucleus (STN) is a brain region that plays a key role in controlling impulsivity. Low neuronal activity in the STN is associated with impulsivity, whereas increased neuronal activity is associated with decreased impulsivity. Therefore, a drug that selectively increases neuronal activity in the STN may offer a new approach for treating ADHD. The NR2D subtype is the main NMDA receptor present in the STN and this receptor subtype is only highly expressed in the STN. Drugs that selectively potentiate NR2D receptors are likely to increase neuronal activity in the STN and decrease impulsive behaviors, while minimizing side effects by avoiding NMDA subtypes in other parts of the brain. Molecules that can potentiate NR2D receptors have been reported. However, these compounds lack sufficient potency and pharmaceutical properties to be suitable drug candidates. The goal of this proposal is to test the feasibility of developing NR2D PAMs that have suitable drug like properties and establish their therapeutic potential by demonstrating efficacy in an animal model of impulsive behavior (the five choice serial reaction time task or 5-CSRTT) that is used industry wide for screening drugs to treat such disorders. To this end, we will undertake an iterative medicinal chemistry program to improve NR2D PAMs for in vivo testing in the 5-CSRTT model of impulsive behavior. Test of Feasibility: the following conditions must be met for feasibility to be shown: 1. NR2D potentiation ED50 < 100 nM; selectivity for NR2D over NR2A-C > 20 fold 2. MW < 500, clogP 1 to 5, H-bond donors < 5; polar surface area 25-100 ¿2 3. Permeability in Caco-2 > 5 cm x 10-6/sec; Protein binding < 99%; asymmetry in MDR1-transfected MDCK cell lines < 2.5 4. Terminal plasma half-life in rat > 1 h after subcutaneous administration, brain/plasma ratio > 0.5, peak free plasma level > 3 X EC50 for NR2D potentiation between 30-60 min post-dose. 5. Dose-dependent inhibition of dopamine D1 agonist-induced locomotor activity 6. Inhibition by 50% of premature responding in the 5-CSRTT. If Phase I is successful, we will apply for Phase II funds to further develop lead compounds and conduct more extensive in vivo efficacy testing that may lead to the filing of an IND.

描述（由适用提供）：这是SBIR I期建议是测试NMDA受体（NR2D PAMS）的NR2D亚型的阳性变构调节剂的可行性，以便治疗冲动性疾病，尤其是ADHD。儿童和成人的多动症患病率估计为4-5％。该疾病通过行为疗法和/或药物治疗；但是，约有80％的患者继续出现未满足的医疗需求。为了满足这一需求，我们正在开发NR2D PAM。丘脑下核us（STN）是一个大脑区域，在控制冲动方面起着关键作用。 STN中的神经元活性低与冲动性有关，而神经元活性的增加与冲动性降低有关。因此，一种选择性增加STN神经元活性的药物可能会提供一种治疗多动症的新方法。 NR2D亚型是STN中存在的主要NMDA受体，该受体亚型仅在STN中高度表达。选择性潜在的NR2D受体的药物可能会增加STN中的神经元活性并降低冲动行为，同时通过避免大脑其他部位的NMDA亚型来最大程度地减少副作用。已经报道了潜在的NR2D受体的分子。但是，这些化合物缺乏足够的效力和药物特性是合适的候选药物。该提案的目的是测试开发具有合适药物诸如特性的NR2D PAM的可行性，并通过在脉冲行为的动物模型（五个选择的序列反应时间任务或5-CSRTT）中证明有效性来确定其治疗潜力，该模型用于筛查药物治疗此类疾病。为此，我们将进行一项迭代医学化学计划，以改善5-CSRTT脉冲行为模型中体内测试的NR2D PAM。可行性测试：必须满足以下条件以使其可行性为显示：1。NR2D增强ED50 <100 nm; NR2A-C上的NR2D的选择性> 20倍2。MW<500，Clogp 1至5，H键供体<5;极地表面积25-100»2 3。渗透性Caco-2> 5 cm x 10-6/sec;蛋白质结合<99％； MDR1转染的MDCK细胞系中的不对称性<2.5 4。在皮下给药后大鼠末端血浆半衰期> 1小时，脑/血浆比率> 0.5，峰值自由血浆> 3 x EC50> 3 x EC50，用于剂量后30-60分钟之间的NR2D稳定性。 5。剂量依赖性抑制多巴胺D1激动剂诱导的运动活性6。在5-CSRTT中抑制50％的早产抑制作用。如果第一阶段成功，我们将申请II期基金，以进一步开发铅化合物并进行更广泛的体内效率测试，这可能导致IND提交。