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.

项目摘要此R01应用名为“用于酒精使用的新型CRFBP-CRFR2复合调节剂的铅优化疾病”是对17-336 PAR的“发现新型脑靶标体内化学探针（R01）的发现”。在美国，饮酒障碍（AUD）影响18岁以上的1510万成年人，是第四可预防的死亡原因。仍有至关重要的需要更有效治疗AUD的治疗剂。压力是AUD开发和维护的重要组成部分。皮质激素释放因子（CRF）在下丘脑 - 垂体 - 肾上腺轴激活中起必不可少的作用并随后释放糖皮质激素响应压力。 CRF通过约束两个受体（CRF1和CRF2）和37 KD CRF结合蛋白[CRFBP（37KD）]。 CRFBP通过 CRF2通过腹侧盖区域（VTA）的作用调节乙醇消耗。我们有证明CRF通过潜在的N-甲基-D-天冬氨酸介导的兴奋性来调节突触输入通过CRFBP/CRF2相互作用在该区域中的突触后电流。最近，我们的数据提出了双重 CRFBP的角色，其中CRFBP（27KD）片段起作用以终止CRF效应和CRFBP （10KD）片段具有潜在的兴奋功能。这些数据支持CRFBP具有的假设超越隔离CRF的功能，其与CRF2的相互作用可能代表 AUD的处理。我们使用束缚受体开发并进行了新的高通量屏幕 CRFBP（10KD）和CRF2之间的复合物，并确定了新型的小分子，CRFBP-CRF2负相对于CRF非竞争性作用的变构调节剂（NAM）。这些NAM不抑制CRF2 在没有CRFBP（10KD）或抑制CRF1的情况下。我们的结构活动关系研究导致铅和备份CRFBP-CRF2 NAM的开发，这些NAM已准备好进行全尺度化学优化提供适合于体内研究的化合物。这，我们的总体目标是开发口头活跃 CRFBP-CRF2调节剂适合于体内概念验证研究，用于治疗AUD。我们的具体目的是：1）设计和合成在体内口服活性的优化的CRFBP-CRF2 NAM； 2）评估相关体外测定中CRFBP-CRF2 NAM的效力和选择性； 3）介绍遗憾， CRFBP-CRF2 NAM在体外和药代动力学中的分布，代谢和排泄（ADME）特性（PK）体内属性； 4）表征铅CRFBP-CRF2 NAM在AUD的离体啮齿动物模型中的问题。生成的CRFBP-CRF2 NAM将为测试CRFBP-CRF2的角色提供强大的工具体内相互作用。更重要的是，我们有充分的位置以发展潜力和选择性小分子具有优化PK特性的CRFBP-CRF2 NAM将用于体内概念验证研究。这多学科研究计划有可能通过贡献来产生重大科学和医学影响为AUD发现新药物。