Novel Neurotensin Analogs as Antischizophrenics

描述（由申请人提供）：这是根据PA-06-079（用于精神疾病的药理学试剂和药物）继续项目“新型神经降压素类似物作为抗精神分裂症药物”（MH-65099）的后续II期SBIR提案。对于精神病的新疗法的鉴定和开发存在关键的临床需求，这是一个主要的未满足的医疗需求。低水平的脑肽神经降压素（NT）与精神分裂症有关，因此可递送至脑的NT受体激动剂具有开发为可能不具有与当前药物相关的副作用的新类别的抗精神病药的显著潜力。在该项目的第一阶段和第二阶段的第一年，从超过50种NT[8 - 13]类似物的综合筛选中，将NT活性片段NT[8 - 13]的衍生物ABS 201确定为最有希望的开发先导物。这种化合物在关键的大鼠精神病模型中表现出很强的疗效，不会引起僵住症，动物也不会对它产生抗药性。最值得注意的是，口服给药时，它在“可药用”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ABS 201，并完成了许多IND使能实验，取得了成功的结果。此外，还成功完成了一系列关键实验，以确定化合物的作用部位和机制。该后续II期的目标是进行必要的活动，以推进ABS 201通过I期临床试验。这将通过完成四个具体目标来实现。在具体目标1中，将进行足量化合物的GMP合成，以完成临床前试验并将其过渡到I期临床试验。在具体目标2中，将完成突出的临床前实验，从而能够准备和提交IND，这是具体目标3的目标。完成I期临床试验是具体目标4的目标。具体目标1将在Genzyme Pharmaceuticals（指定GMP合成实验室）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期试验的研究中心待定。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，拟议的临床试验将是第一个在人类中评估NT衍生物的临床试验。公共卫生相关性：在该项目的I期和II期期间，内源性脑肽神经降压素ABS-201的衍生物已经证明了开发为口服可用的一流抗精神病药所必需的特性。本提案的目标是完成旨在使ABS 201通过I期临床试验的各种活动，包括GMP级材料的合成、临床前药物的完成以及IND的准备和提交。

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.