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: 7089101
• 负责人: THOMAS A DIX
• 金额: $ 47.7万
• 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/7089101
• 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）：低水平的脑肽神经降压素（NT）与精神分裂症有关。因此，穿过血脑屏障的稳定的NT受体激动剂具有开发为可能不具有与当前药物相关的不良副作用的新型抗精神病药的显著潜力。在该项目的I期期间，开发了一种专有的NT激动剂ABS 48，其在IP和口服给药时表现出显著的脑活动，在2种关键的精神分裂症大鼠模型中具有活性，“可用药”ED 50为0.9 mg/kg IP。并且不表现出与其它抗精神病药（抗伤害感受和僵住症）相关的副作用或对重复给药的耐受性。此外，导致发现ABS 48的详尽的结构-活性分析鉴定了另外18种化合物，其具有相对于ABS 48增强的效力和口服活性的潜力。已从私人基金会获得资金，以支持进一步的临床前研究ABS 48。本II期提案的目的是确保剩余的必要资金，以确定最佳先导化合物并完成对先导化合物的临床前研究，以便提交IND，为临床研究做准备。在具体目标1中，18种新化合物将以ABS 48和彼此为基准，以确定用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条件下合成足量的肽先导化合物，以完成特定目标3中的临床前研究，其中将在啮齿动物和犬中进行各种生物利用度、毒性和安全性评价。特定目的2和3将分别由Argolyn Bioscience通过与UCB Bioproducts和MPI Research的分包合同进行。ABS 48具有独特的药理学特征，我们认为它（或从特定目标1的完成中鉴定出的活性更高的衍生物）是最有前途的基于NT的化合物，可用于开发新型抗精神病药物。