Optimization of Drug-like Properties of CRFBP-CRF2 Negative Allosteric Modulators for Alcohol Use Disorder

CRFBP-CRF2 负变构调节剂治疗酒精使用障碍的类药特性优化

基本信息

批准号：
10804469
负责人：
DOUGLAS J SHEFFLER
金额：
$ 85.11万
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：
2023
资助国家：
美国
起止时间：
2023-09-20 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10804469
关键词：
Adult Affect Alcohol consumption Alcohols Amygdaloid structure Area Attention Behavior Therapy Binding Biological Assay Brain C-terminal CRF receptor type 1 CRF receptor type 2 Cause of Death Cell Nucleus Cell surface Cells Cessation of life Chemicals Chemistry Clinical Clinical Trials Collaborations Complex Corticotropin-Releasing Hormone Counseling Data Development Disease Disulfiram Down-Regulation Drug Kinetics Drug Metabolic Detoxication Ethanol dependence Exhibits Genes Glutamates Hypothalamic structure In Vitro Interdisciplinary Study Laboratories Maintenance Measures Mediating Medical Mus N-Methylaspartate N-terminal Naltrexone Pattern Peptides Pharmaceutical Preparations Pharmacotherapy Play Positioning Attribute Property Public Health Rattus Relapse Research Personnel Rodent Model Role Series Social Problems Stress Structure-Activity Relationship Synapses System Testing United States United States Food and Drug Administration Ventral Tegmental Area acamprosate alcohol abuse therapy alcohol use disorder biological adaptation to stress corticotropin releasing factor-binding protein design drug discovery druggable target effective therapy high throughput screening hypothalamic-pituitary-adrenal axis in vivo in vivo evaluation innovation interdisciplinary approach knock-down lead optimization lead series nervous system disorder novel pharmacologic postsynaptic programs protein expression psychologic response small molecule targeted treatment therapeutically effective

项目摘要

PROJECT SUMMARY This application, “Optimization of Drug-like Properties of CRFBP-CRF2 Negative Allosteric Modulators for Alcohol Use Disorder”, is in response to PAR-22-031 “Drug Discovery For Nervous System Disorders (R01 Clinical Trials Not Allowed)”. Alcohol Use Disorder (AUD) remains a huge clinical and public health problem with no effective pharmacological recourse, affecting 28.3 million adults in the United States, and is the 3rd leading preventable cause of death. The only FDA-approved medications for AUD are disulfiram, naltrexone, and acamprosate, all of which exhibit limited efficacy and have limiting contraindications. Hence, there is a critical need to develop more effective therapeutics to treat AUD. While many factors contribute to the development and maintenance of AUD, increasing attention is being paid to potentially druggable targets within the stress system. The primary regulator of the stress response, corticotrophin-releasing factor (CRF), exerts its effects by binding to CRF1 and CRF2 receptors and, also, a secreted 37-kD CRF-binding protein (CRFBP). In addition, CRFBP undergoes spontaneous cleavage into a 27-kD N-terminal fragment, CRFBP(27kD), that binds CRF and a 10- kD C-terminal fragment, CRFBP(10kD), that does not. We hypothesize that CRFBP has dual excitatory and inhibitory effects on CRF function and, thus, ethanol consumption, and that the CRFBP-CRF2 interaction represents a novel pharmacological target for the treatment of AUD. To test this hypothesis, we developed chemical probes specific for the CRFBP(10kD)-CRF2 complex in two lead series that act as negative allosteric modulators (NAMs) of the CRFBP-CRF2 complex only in the presence of CRFBP(10kD). Our recent structure- activity relationship (SAR) studies have provided CRFBP-CRF2 NAMs with good on-target potency and selectivity profiles in vitro, but additional chemical optimization is required to produce chemical probes that are ready for comprehensive in vivo evaluation. These in vivo probes would allow us to establish the role of CRFBP in alcohol consumption and facilitate the development of effective treatments targeting CRFBP for AUD. Thus, our overall objective is to develop systemically active CRFBP-CRF2 NAMs suitable for advanced in vivo proof- of-concept studies for the treatment of AUD. Accordingly, our Specific Aims are: (1) Design and synthesize novel CRFBP-CRF2 NAMs with optimal drug-like properties; (2) Characterize novel CRFBP-CRF2 NAMs in assays measuring potency, selectivity and drug-like properties; and (3) Demonstrate in vivo proof-of-concept for select CRFBP-CRF2 NAMs in rodent models of AUD. The CRFBP-CRF2 NAMs generated will provide powerful in vivo probes for testing the role of the CRFBP-CRF2 interaction in vivo. We are well-positioned to develop potent and selective small molecule CRFBP-CRF2 NAMs with excellent pharmacokinetic properties for in vivo proof-of- concept studies in rodent models of AUD. This multidisciplinary research program has the potential for significant scientific and medical impact by contributing to the discovery of new medications for AUD.

项目摘要此应用，“对CRFBP-CRF2负构构调节剂的类似药物样性能的优化酒精使用障碍”是针对PAR-22-031的“神经系统疾病的药物发现（R01）不允许临床试验）。酒精使用障碍（AUD）仍然是一个巨大的临床和公共卫生问题没有有效的药理识别，影响了美国的2830万成年人，并且是第三名可预防的死亡原因。 AUD的唯一FDA批准药物是二硫仑，纳曲酮和高压素，所有这些都暴露了有限的效率，并且有限制的禁忌症。因此，有关键需要开发更有效的疗法来治疗AUD。尽管许多因素有助于发展和维持AUD，越来越多的注意力正在压力系统内的潜在可吸毒目标。压力反应，皮质营养蛋白释放因子（CRF）的主要调节剂，通过结合执行其效果到CRF1和CRF2受体，以及分泌的37 kD CRF结合蛋白（CRFBP）。另外，CRFBP 将赞助商切解成27 kD的N末端片段，即CRFBP（27KD），该片段结合CRF和10-- KD C末端片段，CRFBP（10KD），没有。我们假设CRFBP具有双重兴奋性和抑制对CRF功能的抑制作用，因此对乙醇的消耗以及CRFBP-CRF2相互作用代表了治疗AUD的新型药物靶标。为了检验这一假设，我们开发了对于两个铅系列中的CRFBP（10KD）-CRF2复合物的化学问题，充当负变构 CRFBP-CRF2复合物的调节剂（NAM）仅在CRFBP（10KD）的情况下。我们最近的结构 - 活动关系（SAR）研究为CRFBP-CRF2 NAM提供了良好的目标效力和在体外的选择性谱，但是需要附加的化学优化才能产生化学问题准备进行全面的体内评估。这些体内问题将使我们能够确定CRFBP的作用在饮酒和支持开发针对CRFBP的有效治疗方法中。那，我们的总体目标是开发适用于体内验证的高级crfbp-crf2 NAMS- 概念治疗AUD的研究。根据我们的具体目的是：（1）设计和合成新颖具有最佳药物样特性的CRFBP-CRF2 NAM；（2）在测定中表征新颖的CRFBP-CRF2 NAMS 测量效力，选择性和类似药物的特性；（3）在体内证明选择 AUD啮齿动物模型中的CRFBP-CRF2 NAM。生成的CRFBP-CRF2 NAM将提供强大的体内在体内测试CRFBP-CRF2相互作用的作用的问题。我们的位置良好，可以发挥潜力和选择性小分子CRFBP-CRF2 NAM具有出色的药代动力学特性，用于体内证明啮齿动物模型中的概念研究。该多学科研究计划有可能科学和医学的影响是通过为AUD发现新药物的贡献。