Lead optimization of novel CRFBP-CRFR2 complex modulators for alcohol use disorder

针对酒精使用障碍的新型 CRFBP-CRFR2 复合调节剂的先导优化

基本信息

批准号：
9920651
负责人：
DOUGLAS J SHEFFLER
金额：
$ 83.6万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
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：
2019-05-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920651
关键词：
Abstinence Adult Affect Age Alcohol consumption Alcohols Amino Acids Amygdaloid structure Area Attention Back Behavior Therapy Binding Binding Proteins Biological Assay Biological Process Brain C-terminal Cause of Death Cell Nucleus Cell surface Cells Cessation of life Chemicals Chemistry Cleaved cell Clinical Clinical Trials Cocaine Complex Conflict (Psychology)Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Counseling Data Development Disulfiram Down-Regulation Drug Kinetics Drug Metabolic Detoxication Drug usage Ethanol Metabolism Ethanol dependence Euphoria Excretory function Frequencies Gene Proteins Glucocorticoids Glutamates Health Hypothalamic structure In Vitro Interdisciplinary Study Laboratories Lead Length Maintenance Mediating Medical Meta-Analysis Metabolism Mus N-Methylaspartate N-terminal Naltrexone Opioid Antagonist Oral Outcome Patients Pattern Peptides Performance Pharmaceutical Preparations Pharmacology Pharmacotherapy Play Positioning Attribute Property Rattus Rodent Model Role Series Social Problems Stress Structure-Activity Relationship Surveys Synapses Synaptosomes System Testing Therapeutic Treatment Efficacy United States United States Food and Drug Administration Ventral Tegmental Area absorption acamprosate alcohol abuse therapy alcohol use disorder base biological adaptation to stress corticotropin releasing factor-binding protein design drinking effective therapy high throughput screening hypothalamic-pituitary-adrenal axis in vitro Assay in vitro activity in vivo innovation lead optimization lead series novel postsynaptic programs psychologic receptor response small molecule tool

项目摘要

Project Summary This R01 application entitled “Lead Optimization of Novel CRFBP-CRFR2 Complex Modulators for Alcohol Use Disorder” is in response to PAR-17-336 “Discovery of in vivo Chemical Probes for Novel Brain Targets (R01)”. In the United States, alcohol use disorder (AUD) affects 15.1 million adults over the age of 18 and is the 4th leading preventable cause of death. There remains a critical unmet need to develop more effective therapeutics to treat AUD. Stress is a significant component in the development and maintenance of AUD. Corticotropin releasing factor (CRF) plays an obligatory role in hypothalamic-pituitary-adrenal axis activation and subsequent release of glucocorticoids in response to stress. CRF exerts its effects by binding to two receptors (CRF1 and CRF2) and a 37 kD CRF binding protein [CRFBP (37kD)]. CRFBP plays a key role via CRF2 in the modulation of ethanol consumption through actions in the ventral tegmental area (VTA). We have demonstrated that CRF modulates synaptic input by potentiating N-methyl-D-aspartate-mediated excitatory postsynaptic currents through CRFBP/CRF2 interactions in this region. More recently, our data suggest a dual role for CRFBP where the CRFBP (27kD) fragment acts to terminate CRF effects and where the CRFBP (10kD) fragment has a potential excitatory function. These data support the hypothesis that CRFBP has functions beyond sequestering CRF and that its interaction with CRF2 may represent a novel target for the treatment of AUD. We developed and performed a novel high-throughput screen utilizing a tethered receptor complex between CRFBP (10kD) and CRF2 and identified novel, small molecule, CRFBP-CRF2 negative allosteric modulators (NAMs) that act noncompetitively with respect to CRF. These NAMs do not inhibit CRF2 in the absence of CRFBP (10kD) or inhibit CRF1. Our structure-activity-relationship studies led to the development of both lead and back-up CRFBP-CRF2 NAMs that are ready for full-scale chemistry optimization to provide compounds suitable for ex vivo studies. Thus, our overall objective is to develop orally active CRFBP-CRF2 modulators suitable for advanced in vivo proof-of-concept studies for the treatment of AUD. Our Specific Aims are: 1) Design and synthesize optimized CRFBP-CRF2 NAMs that are orally active in vivo; 2) Assess the potency and selectivity of CRFBP-CRF2 NAMs in relevant in vitro assays; 3) Profile the absorption, distribution, metabolism, and excretion (ADME) properties of CRFBP-CRF2 NAMs in vitro and pharmacokinetic (PK) properties in vivo; and 4) Characterize lead CRFBP-CRF2 NAM probes in ex vivo rodent models of AUD. The CRFBP-CRF2 NAMs generated will provide powerful tools for testing the role of the CRFBP-CRF2 interaction in vivo. More importantly, we are well-positioned to develop potent and selective small molecule CRFBP-CRF2 NAMs with optimized PK properties that will be utilized for in vivo proof-of-concept studies. This multidisciplinary research program has the potential for significant scientific and medical impact by contributing to the discovery of new medications for AUD.

项目概要该 R01 申请题为“Lead Optimization of Novel CRFBP-CRFR2 Complex Modulators for Drinking Use” Disorder”是对 PAR-17-336“新脑靶点体内化学探针的发现 (R01)”的回应。在美国，酒精使用障碍 (AUD) 影响 1510 万 18 岁以上成年人，是第四大疾病导致可预防的死亡原因仍然迫切需要开发更有效的方法。治疗 AUD 的疗法是 AUD 发生和维持的重要组成部分。促肾上腺皮质激素因子 (CRF) 在下丘脑-垂体-肾上腺轴激活中发挥重要作用随后，CRF 响应压力而释放糖皮质激素，通过与两种物质结合来发挥其作用。受体（CRF1 和 CRF2）和 37 kD CRF 结合蛋白 [CRFBP (37kD)] 通过发挥关键作用。 CRF2 通过腹侧被盖区 (VTA) 的作用调节乙醇消耗。 CRF 通过增强 N-甲基-D-天冬氨酸介导的兴奋性来调节突触输入最近，我们的数据表明该区域通过 CRFBP/CRF2 相互作用产生突触后电流。 CRFBP 的作用，其中 CRFBP (27kD) 片段起到终止 CRF 作用的作用，并且 CRFBP (10kD)片段具有潜在的兴奋功能这些数据支持CRFBP具有的假设。其功能超出了隔离 CRF 的范围，并且它与 CRF2 的相互作用可能代表了 CRF 的一个新靶标我们开发并进行了一种利用束缚受体的新型高通量筛选。 CRFBP (10kD) 和 CRF2 之间的复合物，并鉴定出新型小分子 CRFBP-CRF2 阴性与 CRF 非竞争性作用的变构调节剂 (NAM) 这些 NAM 不会抑制 CRF2。在缺乏 CRFBP (10kD) 或抑制 CRF1 的情况下，我们的结构-活性-关系研究导致了开发主要和备用 CRFBP-CRF2 NAM，为全面化学优化做好准备提供适合离体研究的化合物因此，我们的总体目标是开发口服活性化合物。 CRFBP-CRF2 调节剂适用于治疗 AUD 的先进体内概念验证研究。具体目标是：1) 设计和合成具有口服活性的体内优化 CRFBP-CRF2 NAM；评估 CRFBP-CRF2 NAM 在相关体外测定中的效力和选择性 3) 分析吸收； CRFBP-CRF2 NAM 的体外分布、代谢和排泄 (ADME) 特性和药代动力学 (PK) 体内特性；4) 在 AUD 的离体啮齿动物模型中表征先导 CRFBP-CRF2 NAM 探针。生成的 CRFBP-CRF2 NAM 将为测试 CRFBP-CRF2 的作用提供强大的工具更重要的是，我们有能力开发有效的、选择性的小分子。具有优化 PK 特性的 CRFBP-CRF2 NAM 将用于体内概念验证研究。多学科研究计划有可能通过贡献而产生重大的科学和医学影响发现 AUD 新药。