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