Novel Neurotensin Analogs as Antischizophrenics

作为抗精神分裂症药物的新型神经降压素类似物

• 批准号: 6934060
• 负责人: THOMAS A DIX
• 金额: $ 47.59万
• 依托单位: ARGOLYN BIOSCIENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6934060
• 关键词: amphetamines; antipsychotic agents; apomorphine; biomimetics; dogs; drug adverse effect; drug design /synthesis /production; guinea pigs; hormone receptor; laboratory rat; neurotensin; peptide analog; peptide chemical synthesis; psychopharmacology; receptor binding; schizophrenia

DESCRIPTION (provided by applicant): Low levels of the brain peptide neurotensin (NT) have been linked to schizophrenia. Hence, stable NT receptor agonists that cross the blood brain barrier have significant potential for development as a new class of antipsychotics that may not have the adverse side effects associated with current drugs. During Phase I of this project, a proprietary NT agonist, ABS48, was developed that exhibits significant brain activity when IP and orally dosed, is active in 2 key rat models of schizophrenia at a "druggable" ED50 of 0.9 mg/kg IP., and does not exhibit side effects associated with other antipsychotics (antinociception and catalepsy) or tolerance to repeated dosing. In addition, an exhaustive structure-activity analysis leading to the discovery of ABS48 identified 18 more compounds that have the potential for enhanced potency and oral activity versus ABS48. Funding has been secured from a private foundation to support further preclinical studies of ABS48. The objective of this Phase II proposal is to secure the remaining funding necessary to define the best lead compound and complete preclinical studies on the lead to enable submission of an IND in preparation for clinical studies. In Specific Aim 1, the 18 new compounds will be benchmarked with ABS48 and each other to determine the best lead to commit to the preclinical studies. This will be performed at Argolyn and MUSC. In Specific Aim 2 synthesis of sufficient amounts of the peptide lead will be performed under GMP conditions to enable completion of the preclinical studies in Specific Aim 3, in which various bioavailability, toxicity and safety evaluations will be performed in rodents and dogs. Specific Aims 2 and 3 will be performed by Argolyn Bioscience through subcontracts with UCB Bioproducts and MPI Research, respectively. ABS48 has a unique pharmacologic profile and we believe that it (or a more active derivative identified from completion of Specific Aim 1) is the most promising NT-based compound for development as a novel antipsychotic.

描述(由申请人提供)：低水平的脑多肽神经降压素(NT)与精神分裂症有关。因此，稳定的跨越血脑屏障的NT受体激动剂作为一类新的抗精神病药物具有巨大的发展潜力，可能没有与现有药物相关的不良副作用。在该项目的第一阶段，开发了一种专利的NT激动剂ABS48，该药在ip和口服剂量时显示出显著的大脑活动，在两个关键的精神分裂症大鼠模型中有效，ED50为0.9 mg/kg ip。并且没有表现出与其他抗精神病药物(抗伤害性和惊厥)相关的副作用或对重复剂量的耐受性。此外，导致ABS48发现的详尽的结构-活性分析发现，与ABS48相比，多出了18种化合物，具有增强效力和口服活性的潜力。资金已经从一个私人基金会获得，以支持ABS48的进一步临床前研究。这一第二阶段提案的目标是确保确定最佳铅化合物和完成铅的临床前研究所需的剩余资金，以便能够提交IND，为临床研究做准备。在具体目标1中，18种新化合物将与ABS48和彼此进行基准比较，以确定致力于临床前研究的最佳先导化合物。这将在ArGolyn和MUSC进行。在特定目标2中，将在GMP条件下合成足够量的多肽铅，以完成特定目标3中的临床前研究，其中将在啮齿动物和狗身上进行各种生物利用度、毒性和安全性评估。具体的目标2和3将由ArGolyn Bioscience分别通过与UCB BioProducts和MPI Research的分包合同来执行。ABS48具有独特的药理学特性，我们认为它(或通过完成特定目标1而鉴定的更有活性的衍生物)是最有希望作为新型抗精神病药物开发的NT基化合物。