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
基本信息
- 批准号:9905430
- 负责人:
- 金额:$ 358.89万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2022-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAmphetaminesArrestinsBindingBiochemicalBiological AssayBrainCanis familiarisCardiovascular systemCellsClinicalCocaineCyclic GMPDevelopmentDiseaseDopamineDoseDrug KineticsEnsureEvaluationFormulationG-Protein-Coupled ReceptorsGoalsHumanHypotensionIn VitroIndividualLeadLigandsLiteratureMedicalMiniature SwineModelingMolecular TargetMonitorMonkeysNeuraxisNeurotensinOpioidOralPharmacodynamicsPharmacologyPharmacology StudyPhasePhosphorylationPhysiologicalPhysiologyPlethysmographyPositioning AttributePublic HealthReport (document)ResearchRewardsRodentSafetySelf AdministrationSeriesSignal TransductionSubstance Use DisorderSystemTherapeuticToxicologyUnited StatesVentilatory Depressionaddictionanalogbasebeta-arrestinclinical candidateclinical developmentdrug developmentdrug efficacydrug testingeffective therapyefficacy studyhealthy volunteerhigh riskimprovedin vivoin vivo Modelinduced pluripotent stem celllead candidatemouse modelnatural hypothermianovelopioid use disorderoverdose deathphase 1 studyphase 2 studypostsynaptic neuronspreclinical safetyreceptorreceptor bindingremifentanilscale upside effectstability testingsubstance abuse treatment
项目摘要
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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LAWRENCE S. BARAK其他文献
LAWRENCE S. BARAK的其他文献
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{{ truncateString('LAWRENCE S. BARAK', 18)}}的其他基金
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 - 财政年份:2019
- 资助金额:
$ 358.89万 - 项目类别:
Beta-arrestin Regulation of Ghrelin Signaling in Modulating Addictive Behavior
β-抑制素对 Ghrelin 信号传导在调节成瘾行为中的调节
- 批准号:
8811411 - 财政年份:2014
- 资助金额:
$ 358.89万 - 项目类别:
Beta-arrestin Regulation of Ghrelin Signaling in Modulating Addictive Behavior
β-抑制素对 Ghrelin 信号传导在调节成瘾行为中的调节
- 批准号:
8637290 - 财政年份:2014
- 资助金额:
$ 358.89万 - 项目类别:
Small Molecule Agonsists for the Neurotensin 1 Receptor
神经降压素 1 受体的小分子激动剂
- 批准号:
7845378 - 财政年份:2009
- 资助金额:
$ 358.89万 - 项目类别:
Small Molecule Agonsists for the Neurotensin 1 Receptor
神经降压素 1 受体的小分子激动剂
- 批准号:
7996532 - 财政年份:2009
- 资助金额:
$ 358.89万 - 项目类别:
Molecular fingerprinting of GPCR ligands in Cancer
癌症中 GPCR 配体的分子指纹图谱
- 批准号:
6861075 - 财政年份:2004
- 资助金额:
$ 358.89万 - 项目类别:
Molecular fingerprinting of GPCR ligands in Cancer
癌症中 GPCR 配体的分子指纹图谱
- 批准号:
6783797 - 财政年份:2004
- 资助金额:
$ 358.89万 - 项目类别:
MECHANISMS OF G PROTEIN COUPLED RECEPTOR REGULATION
G 蛋白偶联受体调节机制
- 批准号:
2906525 - 财政年份:1999
- 资助金额:
$ 358.89万 - 项目类别:
MECHANISMS OF G PROTEIN COUPLED RECEPTOR REGULATION
G 蛋白偶联受体调节机制
- 批准号:
6390099 - 财政年份:1999
- 资助金额:
$ 358.89万 - 项目类别:
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