Development of JR-220 (4-Chlorobenzylidenamino-guanidine hydrochloride) as a medication for alcohol dependence

点击翻译按钮获取中文摘要

Abstract Alcohol dependence affects at least 4% of the US population, with a financial cost in excess of $100Bn. Prevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic target, but current treatments are ineffective, and there is an urgent need for new medications. Major factors in causing relapse include the protracted symptoms of withdrawal from alcohol, which are relieved by returning to drinking. Alcohol withdrawal is also implicated in the neurodegeneration that is associated with dependence. There is abundant evidence that the glutamate/NMDA receptor (NMDAR) is a molecular target in alcohol withdrawal, and that inhibitory modulators of the NMDAR are potentially valuable as anti-relapse pharmacotherapy. Target validation identified polyamine enhancement of NMDAR function via the NR2B subunit as a specific target in alcohol withdrawal, and molecular screening identified several lead compounds. JR220 was the most active novel compound from an aryliminoguanidine series, and its cellular effects on neuronal cultures were consistent with NMDAR inhibition via this site. JR220 was then tested in a variety of rodent screens relevant to alcohol dependence, withdrawal and neurotoxicity, including several screens in other laboratories. The drug was highly active in all of these screens, with a potency 5-200x that of acamprosate, which is FDA-approved for the prevention of relapse. JR220 caused mild sedation at higher doses, but there was no overt toxicity even on repeated administration. Pharmacokinetic studies in the rat showed dose dependent elevations of concentrations in plasma after intraperitoneal, subcutaneous and oral administration (oral bioavailability >70%). Concentrations obtained in brain were ~10x higher than plasma, suggesting an active uptake system at the blood/brain barrier. On repeated once daily dosing for 7 days, JR220 did not accumulate in plasma or brain, and no overt toxicity was observed. The only concern is that the plasma half-life following oral administration may be too short for once-a-day dosing in relapse prevention. This can be addressed by formulation as an oral extended release formulation or by a transdermal patch (which would also have other advantages for treatment of alcohol use disorders). Intellectual property in JR220 as a treatment for aspects of alcohol withdrawal and the transdermal patch formulation of JR220 are covered by provisional applications to the USPTO. The preliminary data indicates that JR220 is an excellent candidate as an anti-relapse medication, and the current proposal is to develop the drug further for this use. The aim is now to complete the studies required prior to submission of the drug to the FDA for consideration as an investigational new drug (IND). Thus, in the proposed studies we will complete investigation of metabolism and metabolite identification in vitro, and Absorption, Distribution, Metabolism, and Excretion in vivo. The studies will also include a screen for off target actions and studies on safety and toxicology in two species. These studies will include escalating acute dose studies, and sub-chronic studies (to reflect the maintenance of patients on anti-relapse medication). JR220 will be produced under GMP conditions, and production scaled up to meet requirements for future human trials. If an IND designation is obtained, the objective will then be to partner with a major pharmaceutical company in testing the drug in a human safety trial, and then in clinical trials in alcohol dependent volunteers. The objective is to develop JR220 for relapse prevention and neuroprotection to provide a pharmacotherapy that is more effective for these therapeutic targets than others currently available.