Novel Neurotensin Analogs as Antischizophrenics

描述（由申请人提供）：这是继续PA-06-079（精神障碍药理制剂和药物）项目“新型神经紧张素类似物作为抗精神分裂症药物”（MH-65099）的后续二期SBIR提案。临床迫切需要鉴定和开发治疗精神病的新疗法，这是一个尚未得到满足的主要医疗需求。低水平的脑肽神经紧张素（NT）与精神分裂症有关，因此NT受体激动剂可以被输送到大脑，作为一种新的抗精神病药物有很大的发展潜力，可能没有目前药物相关的副作用。在该项目的第一阶段和第二阶段的第一年，从50多个NT[8-13]类似物的综合筛选中，NT活性片段NT的衍生物ABS201被确定为最有希望开发的先导物。该化合物在关键精神病大鼠模型中表现出较强的疗效，不引起猝厥，动物不产生耐药性。最值得注意的是，口服时，它在“可用药”剂量下具有活性。在II期提案的其余部分，完成了详细的临床前和临床计划，以进一步开发ABS201，并完成了许多使ind成为可能的实验，并取得了成功的结果。此外，成功地完成了一组关键的实验，以确定该化合物的作用位点和作用机制。这个后续II期的目标是执行推进ABS201通过I期临床试验所需的活动。这将通过完成四个具体目标来实现。在Specific Aim 1中，将进行足够量的化合物的GMP合成，以完成临床前试验并将其过渡到I期临床试验。在Specific Aim 2中，杰出的临床前实验将完成，从而实现IND的准备和提交，这是Specific Aim 3的目标。完成I期临床试验是Specific Aim 4的目标。Specific Aim 1将在指定的GMP合成实验室Genzyme Pharmaceuticals完成。Specific Aim 2将由Argolyn与Summit Drug Development（撰写临床计划）合作管理，使用高质量的cro进行实验。具体目标3和4将由Argolyn和Summit管理，I期试验的地点有待确定。在过去的30年里，将NT与精神分裂症联系起来的证据已经积累起来，这项拟议的临床试验将是首次在人类中评估NT衍生物。公共卫生相关性：在该项目的I期和II期，内源性脑肽神经紧张素的衍生物ABS-201已显示出作为口服的一流抗精神病药开发所必需的特性。完成旨在使ABS201通过I期临床试验的各种活动，包括gmp级材料的合成、临床前的完成以及IND的准备和提交，是本提案的目标。

DESCRIPTION (provided by applicant): This is the follow-on Phase II SBIR proposal to continue the project "Novel Neurotensin Analogs as Antischizophrenics" (MH-65099) under PA-06-079 (Pharmacological Agents and Drugs for Mental Disorders). There exists a critical clinical need for the identification and development of novel therapies for psychosis, a major unmet medical need. Low levels of the brain peptide neurotensin (NT) have been linked to schizophrenia, hence NT receptor agonists that can be delivered to the brain have significant potential for development as a new class of antipsychotics that might not have the side- effects associated with current drugs. In Phase I and the first year of Phase II of this program, ABS201, a derivative of the active fragment of NT, NT[8-13], was identified as the most promising lead for development from a comprehensive screen of over 50 NT[8-13] analogs. This compound showed strong efficacy in the key rat models of psychosis, did not cause catalepsy, and animals did not develop resistance to it. Most notably, it is active at a "druggable" dose when administered orally. During the rest of the Phase II proposal, a detailed preclinical and clinical plan was completed for further development of ABS201, and many of the IND-enabling experiments were completed with successful outcomes. In addition, a critical set of experiments to define the site and mechanism of action of the compound was completed successfully. The goal of this follow-on Phase II is to perform activities necessary for advancing ABS201 through Phase I of clinical trials. This will be achieved through completion of four Specific Aims. In Specific Aim 1, GMP synthesis of sufficient amounts of the compound to finish preclinicals and bridge it into the Phase I clinical trial will be performed. In Specific Aim 2 the outstanding preclinical experiments will be completed enabling preparation and submission of the IND, the goal of Specific Aim 3. Completion of the Phase I clinical trial is the objective of Specific Aim 4. Specific Aim 1 will be completed at Genzyme Pharmaceuticals, the designated GMP synthesis laboratory. Specific Aim 2 will be managed by Argolyn in collaboration with Summit Drug Development (who wrote the clinical plan) using high quality CROs to perform the experiments. Specific Aims 3 and 4 will be managed by Argolyn and Summit with the site(s) of the Phase I trials to be determined. Evidence linking NT to schizophrenia has accumulated over the last 30 years, the proposed clinical trial would be the first in which a NT derivative is evaluated in humans. PUBLIC HEALTH RELEVANCE: During Phase I and II of this project a derivative of the endogenous brain peptide neurotensin, ABS-201, has demonstrated the characteristics necessary for development as an orally available, first-in-class antipsychotic. Completion of various activities designed to take ABS201 through Phase I of clinical trials, including synthesis of GMP-grade material, completion of preclinicals, and the preparation and submission of an IND, is the goal of this proposal.