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.

项目概要该申请“优化 CRFBP-CRF2 负变构调节剂的类药特性酒精使用障碍”，是对 PAR-22-031“神经系统疾病药物发现 (R01 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物追索，影响了美国 2830 万成年人，是第三大主要疾病 FDA 批准的唯一可预防 AUD 的药物是双硫仑、纳曲酮和阿坎酸，所有这些都表现出有限的功效并且具有有限的禁忌症，因此，存在一个关键的问题。需要开发更有效的疗法来治疗 AUD，而许多因素导致了 AUD 的发生和发展。随着 AUD 的维持，人们越来越关注压力系统内潜在的可药物靶点。应激反应的主要调节因子促肾上腺皮质激素释放因子 (CRF) 通过结合来发挥其作用 CRF1 和 CRF2 受体以及分泌的 37-kD CRF 结合蛋白 (CRFBP)。自发裂解成 27-kD N 端片段 CRFBP(27kD)，该片段结合 CRF 和 10- kD C 末端片段，CRFBP(10kD)，我们认为 CRFBP 具有双重兴奋性和兴奋性。对 CRF 功能以及乙醇消耗的抑制作用，以及 CRFBP-CRF2 相互作用代表了治疗 AUD 的新药理学靶点为了检验这一假设，我们开发了。两个先导系列中的 CRFBP(10kD)-CRF2 复合物特异性化学探针，充当负变构 CRFBP-CRF2复合物的调节剂（NAM）仅在CRFBP（10kD）存在的情况下进行。活性关系（SAR）研究为 CRFBP-CRF2 NAM 提供了良好的靶向效力和体外选择性概况，但需要额外的化学优化来生产化学探针这些体内探针将使我们能够确定 CRFBP 的作用。饮酒并促进针对 AUD 的 CRFBP 的有效治疗方法的开发。我们的总体目标是开发适用于高级体内验证的系统活性 CRFBP-CRF2 NAM 因此，我们的具体目标是：（1）设计和合成新颖的药物。 (2) 在测定中表征新型 CRFBP-CRF2 NAM 测量效力、选择性和类药特性；以及 (3) 展示选定的体内概念验证 AUD 啮齿动物模型中的 CRFBP-CRF2 NAM 生成的 CRFBP-CRF2 NAM 将提供强大的体内功能。用于测试 CRFBP-CRF2 体内相互作用作用的探针我们有能力开发有效且有效的探针。选择性小分子 CRFBP-CRF2 NAM 具有出色的药代动力学特性，可用于体内验证 AUD 啮齿动物模型的概念研究这一多学科研究项目具有重大潜力。为 AUD 新药物的发现做出贡献，从而产生科学和医学影响。