Development of SBI-553, an allosteric modulator of NTR1, for the treatment of substance use disorders

开发 SBI-553（一种 NTR1 变构调节剂），用于治疗物质使用障碍

• 批准号: 10909417
• 负责人: LAWRENCE S. BARAK
• 金额: $ 501.45万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10909417
• 关键词: Development; SBI; 553; allosteric; modulator

PROJECT SUMMARY Opioid use disorder (OUD) is a major public health crisis in the United States, with >50,000 overdose deaths in 2017 alone. Addiction to opioids is intimately related to the physiology of the brain’s dopamine-based rewarding system. The neurotensin 1 receptor (NTR1) is found among dopamine pre and post-synaptic neurons in the central nervous system, and acts as a modulator of dopaminergic systems. Even though substantial evidence points towards NTR1 as a molecular target for treating addiction disorders, few non- peptide brain penetrant neurotensin modulators have been identified, and orthosteric NTR1 ligands display side effects including hypotension and hypothermia that have limited their clinical development. Recently, we have discovered a series of brain-penetrant NTR1 modulators, including a lead compound SBI-553, with a unique mechanism of action at NTR1. SBI-553 is an orally available and brain penetrant b-arrestin biased allosteric modulator of NTR1, which shows efficacy in a range of addiction models. The literature contains no documented reports of such molecules among positive or negative allosteric modulators of GPCRs. In addition, the unique profile of SBI-553 appears to circumvent the clinically limiting side effects of hypothermia and hypotension displayed by orthosteric NTR1 ligands. While potentially high risk, the activity of SBI-553 has been validated in vitro and in vivo, and the initial safety profiling indicates no issues that would preclude further development. The goal of the application is to develop SBI-553 as a treatment for opioid use disorders. A 2-year UG3 phase is proposed with the primary objective of determining the suitability of SBI-553 (or a backup compound) entering IND-enabling studies followed by a 2-year UH3 phase with the primary objective of completing a Phase 1 single ascending dose study. During the UG3 phase, the team will complete pharmacokinetic (PK) studies and the preclinical safety profile of SBI-553 in a relevant species; identify a backup compound to SBI-553; and conduct definitive cellular and in vivo pharmacology studies with SBI-553 (and/or potential backup) in models of addiction to inform best clinical indication and clinical endpoints (PK/pharmacodynamic). During the UH3 Phase, the team will ensure completion of GMP Synthesis, Stability Testing and Formulation; GLP Toxicology studies; and the Phase 1 single ascending dose study.

项目总结 阿片类药物使用障碍(OUD)是美国一项主要的公共卫生危机，每年有5万人死于过量服药。 仅2017年。阿片成瘾与大脑以多巴胺为基础的生理密切相关 奖励制度。神经降压素1受体(NTR1)存在于突触前和突触后的多巴胺中 中枢神经系统中的神经元，并作为多巴胺能系统的调节器。即使 大量证据表明，NTR1是治疗成瘾障碍的分子靶点，很少有非 多肽脑穿透性神经降压素调节剂已被鉴定，并显示正构体NTR1配体 包括低血压和低体温在内的副作用限制了它们的临床发展。最近，我们 已经发现了一系列脑穿透性NTR1调节剂，包括一种铅化合物SBI-553，它具有 NTR1独特的作用机制。SBI-553是一种口服和脑渗透剂b-arrestin偏向 NTR1的变构调节剂，在一系列成瘾模型中显示出有效性。这部文学作品没有包含任何 关于GPCRs的正负变构调节剂中此类分子的文献报道。此外, SBI-553的独特特性似乎可以避免临床上有限的低温副作用和 正构体NTR1配体显示的低血压。虽然可能存在高风险，但SBI-553的活动一直是 在体外和体内进行了验证，初步的安全性分析表明没有任何问题会阻止进一步 发展。该申请的目标是开发SBI-553作为治疗阿片类药物使用障碍的药物。 提出了一个为期2年的UG3阶段，主要目标是确定SBI-553(或 后备化合物)进入支持IND的研究，然后是为期2年的UH3阶段，主要目标是 完成一期单次递增剂量研究。 在UG3阶段，该团队将完成药代动力学(PK)研究和临床前安全性概况 在相关物种中发现SBI-553；确定SBI-553的备用化合物；并在 在成瘾模型中使用SBI-553(和/或潜在备份)的体内药理学研究为最佳临床提供信息 适应症和临床终点(PK/药效学)。在UH3阶段，团队将确保 完成GMP合成、稳定性测试和配方；GLP毒理学研究；以及第一阶段 单次递增剂量研究。