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

项目摘要 阿片类药物使用障碍（OUD）是美国的一个主要公共卫生危机，在美国有超过50，000例过量死亡。 仅2017年。阿片类药物成瘾与大脑中以多巴胺为基础的 奖励制度神经降压素1受体（NTR 1）存在于多巴胺突触前和突触后， 中枢神经系统中的神经元，并作为多巴胺能系统的调节剂。即使 大量证据表明NTR 1是治疗成瘾性疾病的分子靶点， 已经鉴定了肽脑渗透性神经降压素调节剂，并且正构NTR 1配体显示 副作用包括低血压和体温过低，这限制了它们的临床发展。最近我们 已经发现了一系列脑渗透NTR 1调节剂，包括一种先导化合物SBI-553， NTR 1的独特作用机制。SBI-553是一种口服的脑渗透剂， NTR 1的变构调节剂，其在一系列成瘾模型中显示出功效。文献中没有 在GPCR的正或负变构调节剂中记录了此类分子的报道。此外，本发明还提供了一种方法， SBI-553的独特特性似乎避免了低温的临床限制性副作用， 正构NTR 1配体显示的低血压。虽然潜在的高风险，但SBI-553的活动一直是 经体外和体内验证，初步安全性分析表明没有问题， 发展该申请的目标是开发SBI-553作为阿片类药物使用障碍的治疗方法。 建议为期2年的UG 3阶段，主要目标是确定SBI-553（或 备用化合物）进入IND使能研究，随后进入2年UH 3期，主要目的是 完成1期单次剂量递增研究。 在UG 3阶段，该团队将完成药代动力学（PK）研究和临床前安全性特征， SBI-553在相关物种中的作用;确定SBI-553的备用化合物;并在相关物种中进行确定性的细胞和免疫学研究。 在成瘾模型中进行SBI-553（和/或潜在备份）的体内药理学研究，以提供最佳临床 适应症和临床终点（PK/药效学）。在UH 3阶段，团队将确保 完成GMP合成、稳定性试验和配制; GLP毒理学研究;以及I期 单次剂量递增研究。

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.