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: 7254117
• 负责人: THOMAS A DIX
• 金额: $ 39.25万
• 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 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7254117
• 关键词: Adverse effects; Agonist; Animals; Antipsychotic Agents; Benchmarking; Biological Availability; Blood - brain barrier anatomy; Brain; Canis familiaris; Catalepsy; Charge; Class; Clinical Research; Commit; Condition; Development; Diabetes Mellitus; Disease remission; Dose; Evaluation; Excision; Exhibits; Foundations; Funding; Funding Agency; Generations; Guanosine Monophosphate; Lead; Link; Lipids; Literature; Medical; Modeling; N-terminal; Neuraxis; Neurobehavioral Manifestations; Neurotensin; Neurotensin Receptors; Oral; Pain; Pathology; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Preparation; Property; Rattus; Reporting; Research; Research Institute; Rodent; Safety; Schizophrenia; Secure; Series; Serum; Structure; Symptoms; Time; Toxic effect; United States Food and Drug Administration; Weight Gain; analog; antischizophrenic; attenuation; atypical antipsychotic; base; experience; human SLPI protein; lipophilicity; methyl group; neurotensin 69L; novel; novel strategies; preclinical study; receptor; receptor binding; response

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）：低水平的脑肽神经紧张素（NT）与精神分裂症有关。因此，能穿过血脑屏障的稳定的NT受体激动剂作为一种新型抗精神病药物具有巨大的发展潜力，这种抗精神病药物可能没有现有药物的不良副作用。在这个项目的第一阶段，一种专有的NT激动剂ABS48被开发出来，当IP和口服给药时，它显示出显著的大脑活动，在2个关键的精神分裂症大鼠模型中，“可用药”的ED50为0.9 mg/kg IP。并且不表现出与其他抗精神病药物（抗癫痫和抗癫痫）相关的副作用或对重复给药的耐受性。此外，通过详尽的结构-活性分析，发现了18种与ABS48相比具有更高效力和口服活性的化合物。已从一家私人基金会获得资金，以支持ABS48的进一步临床前研究。该II期提案的目标是确保剩余的资金，以确定最佳先导化合物并完成先导物的临床前研究，以便提交IND，为临床研究做准备。在Specific Aim 1中，18种新化合物将以ABS48和其他化合物为基准，以确定用于临床前研究的最佳先导物。这将在Argolyn和MUSC进行。在Specific Aim 2中，将在GMP条件下合成足够量的肽铅，以完成Specific Aim 3的临床前研究，其中将在啮齿动物和狗中进行各种生物利用度，毒性和安全性评估。具体目标2和3将分别由Argolyn Bioscience通过与UCB Bioproducts和MPI Research的分包合同执行。ABS48具有独特的药理学特征，我们相信它（或从完成Specific Aim 1中鉴定出的更有活性的衍生物）是最有希望发展为新型抗精神病药物的nt基化合物。