Development of a Novel Medication for Alcohol Use Disorder with an Active IND Dual Inhibitor of T-Type Calcium Channel and Soluble Epoxide Hydrolase

点击翻译按钮获取中文摘要

7. SUMMARY Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide and often co-occurs with chronic pain, anxiety, depression, and opioid dependence. Unfortunately, currently available medications for AUD have limited efficacy with unwanted side effects. To address this unmet medical need, we propose an SBIR Phase I U43 project in response to PAR-22-102 "Investigational New Drug (IND)-enabling and Early-Stage Development of Medications to Treat Alcohol Use Disorder and Alcohol-Associated Organ Damage." Our project will focus on proof-of-concept studies of our active IND (157314), AFA-281, a novel dual inhibitor of T-type calcium channels (Cav3) and soluble epoxide hydrolase (sEH), for AUD treatment. These proof-of-concept studies would use well-established rodent AUD models and testing paradigms. AfaSci discovered AFA-281 from a series of patented dual modulators of Cav3 channels and sEH as a non- opioid analgesic. We completed lead identification through rational drug design and iterative screenings using patch-clamp recordings and enzymatic assays. Lead optimization was conducted, including selectivity screening on hERG and key cardiac ion channels, and CEREP proofing of 81 off-drug targets. These screenings together with studies using human cardiomyocytes ex vitro demonstrated that AFA-281 has no cardiac safety concerns. In pharmacokinetic and pharmacodynamic (PK/PD) studies, AFA-281 has shown excellent oral bioavailability, acceptable t1/2, CNS penetration, broad analgesic effects on neuropathic and inflammatory pain, and good safety margins. Recently, AFA-281's IND application was accepted by the FDA for a lead indication of neuropathic pain. Our preliminary studies on AUD have demonstrated that AFA-281 is capable of decreasing alcohol intake, binge drinking and preference, and suppressing alcohol-seeking behavior in rodents. In this proposed SBIR Phase I U43 project, we will conduct preclinical proof-of-concept studies to investigate AFA-281's effects on AUD, and its associated chronic pain and negative affective disorders, such as anxiety and depression in rats via three Specific Aims. Aim 1 will evaluate PK/PD of AFA-281 in reducing alcohol consuming and seeking behavior via operant self-administration. Aim 2 will investigate AFA-281's effects on hyperalgesia, anxiety, and depression in rats withdrawn from chronic alcohol consumption. Aim 3 will explore the mechanism of action of AFA-281 underlying its efficacy in AUD via assessing AFA-281’s modulation on alcohol-altered neural activity indicated by c-Fos expression and brain neuroinflammation, and evaluation of Cav3 channel activity, and cell excitability in the lateral habenula, a brain area implicated in AUD. Success in our Phase I project would demonstrate that AFA-281 can reduce alcohol consumption and seeking behavior, provide an evidence base to prepare for the transition to clinical proof-of-concept studies in the U44 SBIR project. Given the significant public health burden of AUD, developing a more effective and safe medication accessible for treatment and prevention of AUD would have a considerable positive impact on public health.