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

项目摘要 本申请，“优化CRFBP-CRF 2负变构调节剂的药物样性质， 酒精使用障碍”，是对PAR-22-031“神经系统疾病药物发现（R 01）”的回应 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， 没有有效的药物资源，影响了美国2830万成年人，是第三大 可预防的死亡原因FDA批准的唯一治疗AUD的药物是双硫仑，纳洛酮， 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，有一个关键的 需要开发更有效的治疗方法来治疗AUD。虽然许多因素有助于发展， 随着AUD的维持，越来越多的注意力被放在应激系统中的潜在药物靶点上。 促肾上腺皮质激素释放因子（CRF）是应激反应的主要调节因子， CRF 1和CRF 2受体，以及分泌的37-kD CRF结合蛋白（CRFBP）。此外，CRFBP 发生自发切割成27 kD的N-末端片段CRFBP（27 kD），其结合CRF和10- kD的C-末端片段，CRFBP（10 kD），不。我们假设CRFBP具有双重兴奋性， 对CRF功能的抑制作用，因此，乙醇消耗，以及CRFBP-CRF 2相互作用 代表了治疗AUD的新药理学靶点。为了验证这一假设，我们开发了 CRFBP（10 kD）-CRF 2复合物特异性化学探针，在两个铅系列中起负变构作用 CRFBP-CRF 2复合物的调节剂（NAM）仅在CRFBP（10 kD）存在下。我们最近的结构- 活性关系（SAR）研究提供了具有良好靶向效力的CRFBP-CRF 2 NAM， 选择性曲线，但需要额外的化学优化来产生 准备进行全面的体内评价。这些体内探针将使我们能够建立CRFBP的作用， 在酒精消费和促进开发有效的治疗靶向CRFBP的AUD。因此，在本发明中， 我们的总体目标是开发适合于先进的体内验证的全身活性CRFBP-CRF 2 NAM， 治疗AUD的概念研究。因此，我们的具体目标是：（1）设计合成新的 具有最佳药物样性质的CRFBP-CRF 2 NAM;（2）在测定中表征新型CRFBP-CRF 2 NAM 测量效力、选择性和药物样性质;和（3）证明选择性的体内概念验证 AUD啮齿动物模型中的CRFBP-CRF 2 NAM。产生的CRFBP-CRF 2 NAM将提供强大的体内 用于测试体内CRFBP-CRF 2相互作用的作用的探针。我们有能力开发强大的， 选择性小分子CRFBP-CRF 2 NAM，具有优异的药代动力学特性，可用于体内验证 AUD啮齿动物模型的概念研究。这项多学科研究计划具有重大的潜力 科学和医学的影响，有助于发现新的药物治疗AUD。

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.