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

项目总结 本应用题为《CRFBP-CRF2负变构调节剂的类药物性能优化》。 酒精使用障碍“，是对PAR-22-031《神经系统疾病药物发现》(R01)的响应 不允许进行临床试验)“。酒精使用障碍(AUD)仍然是一个巨大的临床和公共卫生问题 没有有效的药理途径，在美国影响着2830万成年人，是第三大 可预防的死因。FDA批准的唯一治疗AUD的药物是双硫兰、纳曲酮和 氨基己酸酯，所有这些药物都表现出有限的疗效和有限的禁忌症。因此，有一个关键的 需要开发更有效的疗法来治疗AUD。虽然许多因素促进了经济的发展和 随着澳元的维持，应激系统内潜在的可用药靶点正受到越来越多的关注。 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 与CRF1和CRF2受体结合，以及分泌37kD的CRF结合蛋白(CRFBP)。此外，CRFBP 自发裂解成27 kD的N末端片段CRFBP(27kD)，它结合CRF和一个10- Kd C-末端片段，CRFBP(10kD)，没有。我们假设CRFBP具有兴奋性和双重兴奋性 抑制CRF功能，从而抑制酒精消耗，以及CRFBP-CRF2相互作用 为AUD的治疗提供了一个新的药理靶点。为了检验这一假设，我们开发了 CRFBP(10kD)-CRF2络合物在两个铅系列中作为负变构作用的化学探针 仅在CRFBP(10kD)存在的情况下，CRFBP-CRF2复合体的调制器(NAM)。我们最近的结构- 活性关系(SAR)研究为CRFBP-CRF2 NAMS提供了良好的靶向效力和 体外选择性分布，但需要额外的化学优化才能生产出符合以下条件的化学探针 准备好进行全面的体内评估。这些活体探测将使我们能够确定CRFBP的作用 减少酒精消费，促进针对慢性阻塞性肺疾病的有效治疗方法的开发。因此， 我们的总体目标是开发具有系统活性的CRFBP-CRF2 NAMS，适用于先进的活体验证- AUD治疗的概念性研究。因此，我们的具体目标是：(1)设计和合成小说 具有最佳类药物性质的CRFBP-CRF2纳米微球；(2)新型CRFBP-CRF2纳米微球的检测表征 测量效力、选择性和类药物特性；以及(3)展示体内选择的概念验证 CRFBP-CRF2NAMS在AUD啮齿动物模型中的表达产生的CRFBP-CRF2 NAMS将在体内提供强大的 探讨CRFBP-CRF2相互作用在体内的作用。我们处于有利地位，可以开发出强大的 具有良好药代动力学特性的选择性小分子CRFBP-CRF2纳米粒用于体内验证 AUD啮齿动物模型的概念研究。这一多学科的研究计划有可能对 通过为发现治疗澳门氏症的新药做出贡献，从而产生科学和医学影响。

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.