Discovery, characterization and preclinical development of pro-neurogenic drugs

促神经源性药物的发现、表征和临床前开发

• 批准号: 8461707
• 负责人: STEVEN L MCKNIGHT
• 金额: $ 118.44万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461707
• 关键词: Adult; Age-associated memory impairment; Animal Model; Attention; Bioavailable; Biochemical; Biological Assay; Birth; Blood - brain barrier anatomy; Brain; Brain region; Chemicals; Cognition; Cognitive; Cognitive deficits; Decision Making; Development; Dose; Environment; Failure; Fibroblast Growth Factor; Functional disorder; Genes; Genetic Transcription; Goals; Half-Life; Hippocampal Formation; Hippocampus (Brain); Human; Impaired cognition; Laboratories; Laboratory mice; Learning; Life; Link; Mediating; Memory; Mental disorders; Methods; Molecular Target; Motivation; Mus; Nature; Neurobehavioral Manifestations; Neurons; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Population; Positioning Attribute; Psyche structure; Regulatory Pathway; Reporting; Research Personnel; Running; Schizophrenia; Site; Social Interaction; Therapeutic; Toxic effect; Treatment Efficacy; Work; age related; base; birth control; dentate gyrus; design; human disease; in vitro Assay; in vivo; mental age; neurogenesis; novel therapeutics; postnatal; pre-clinical; screening; small molecule; success

DESCRIPTION (provided by applicant): Cognitive deficits in learning, memory, attention and decision-making represent chronically disabling aspects of many forms of mental illness, including schizophrenia. Age-related decline in cognitive abilities can also be debilitating to a substantial fraction of the human population. Cognitive dysfunction has been linked to deficient functioning of the hippocampal formation of the brain. The dentate gyrus, as part of the hippocampal formation, represents a site where new neurons are formed on a regular basis in the adult brain. Studies in laboratory mice have shown that the rate of new neuron formation in the dentate gyrus is stimulated by healthy activities such as wheel running, access to an enriched environment, and access to social interaction. It is hypothesized that pharmacological agents that specifically augment dentate gyrus-specific neurogenesis may benefit patients suffering from cognitive deficits. Over the past three years the investigators authoring this application have conducted an unbiased in vivo screen to identify drug-like chemicals capable of stimulating hippocampal neurogenesis. These efforts have led to the discovery of eight distinct, pro-neurogenic compounds. One of these compounds has been found to be orally bioavailable, endowed with a favorable half life, capable of crossing the blood brain barrier, and devoid of toxicity following multi-month administration at a level 10X the minimal therapeutic dose. Detailed studies have shown that this most advanced compound enhances both the birth and survival of hippocampal neurons. The putative efficacies of these eight compounds are being studied in an animal model of schizophrenia unique to the laboratory of the investigators. Likewise, biochemical methods will be employed to identify the molecular targets of as many of the eight pro-neurogenic compounds as possible. It is hoped that this work will provide a basis for the discovery of new treatment options for patients suffering from cognitive deficits associated with mental illness.

描述（由申请人提供）：学习、记忆、注意力和决策方面的认知缺陷代表了许多形式的精神疾病（包括精神分裂症）的慢性致残方面。与认知能力相关的认知能力下降也可能使相当一部分人衰弱。认知功能障碍与大脑海马结构的功能缺陷有关。齿状回，作为海马结构的一部分，代表了成人大脑中定期形成新神经元的部位。对实验室小鼠的研究表明，齿状回中新神经元形成的速度受到健康活动的刺激，如车轮运行，进入丰富的环境和社会互动。据推测，特异性增强齿状回特异性神经发生的药理学药物可能有益于患有认知缺陷的患者。在过去的三年里，撰写本申请的研究人员进行了无偏见的体内筛选，以确定能够刺激海马神经发生的药物样化学物质。这些努力导致了八种不同的前神经原性化合物的发现。已经发现这些化合物之一是口服生物可利用的，具有有利的半衰期，能够穿过血脑屏障，并且在以10倍最小治疗剂量的水平施用多个月后没有毒性。详细的研究表明，这种最先进的化合物增强了海马神经元的出生和存活。这八种化合物的推定效力正在研究中的精神分裂症的动物模型独特的研究人员的实验室。同样，将采用生物化学方法来鉴定尽可能多的八种前神经原性化合物的分子靶点。希望这项工作将为发现与精神疾病相关的认知缺陷患者的新治疗方案提供基础。

项目成果

P7C3 neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salvage.

• DOI: 10.1016/j.cell.2014.07.040
• 发表时间: 2014-09-11
• 期刊: Cell
• 影响因子: 64.5
• 作者: Wang G;Han T;Nijhawan D;Theodoropoulos P;Naidoo J;Yadavalli S;Mirzaei H;Pieper AA;Ready JM;McKnight SL
• 通讯作者: McKnight SL

Discovery of a neuroprotective chemical, (S)-N-(3-(3,6-dibromo-9H-carbazol-9-yl)-2-fluoropropyl)-6-methoxypyridin-2-amine [(-)-P7C3-S243], with improved druglike properties.

• DOI: 10.1021/jm401919s
• 发表时间: 2014-05-08
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Naidoo J;De Jesus-Cortes H;Huntington P;Estill S;Morlock LK;Starwalt R;Mangano TJ;Williams NS;Pieper AA;Ready JM
• 通讯作者: Ready JM

P7C3 and an unbiased approach to drug discovery for neurodegenerative diseases.

• DOI: 10.1039/c3cs60448a
• 发表时间: 2014-10-07
• 期刊: Chemical Society reviews
• 影响因子: 46.2
• 作者: Pieper AA;McKnight SL;Ready JM
• 通讯作者: Ready JM