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

Abstract Alcohol dependence affects at leastof the US populationwith a financial cost in excess of $BnPrevention of relapse in patients attempting to reduce alcohol consumption is a major therapeutic targetbut current treatments are ineffectiveand there is an urgent need for new medicationsMajor factors in causing relapse include the protracted symptoms of withdrawal from alcoholwhich are relieved by returning to drinkingAlcohol withdrawal is also implicated in the neurodegeneration that is associated with dependenceThere is abundant evidence that the glutamate NMDA receptorNMDARis a molecular target in alcohol withdrawaland that inhibitory modulators of the NMDAR are potentially valuable as anti relapse pharmacotherapyTarget validation identified polyamine enhancement of NMDAR function via the NR B subunit as a specific target in alcohol withdrawaland molecular screening identified several lead compoundsJRwas the most active novel compound from an aryliminoguanidine seriesand its cellular effects on neuronal cultures were consistent with NMDAR inhibition via this siteJRwas then tested in a variety of rodent screens relevant to alcohol dependencewithdrawal and neurotoxicityincluding several screens in other laboratoriesThe drug was highly active in all of these screenswith a potencyx that of acamprosatewhich is FDA approved for the prevention of relapseJRcaused mild sedation at higher dosesbut there was no overt toxicity even on repeated administrationPharmacokinetic studies in the rat showed dose dependent elevations of concentrations in plasma after intraperitonealsubcutaneous and oral administrationoral bioavailability rtConcentrations obtained in brain werex higher than plasmasuggesting an active uptake system at the blood brain barrierOn repeated once daily dosing fordaysJRdid not accumulate in plasma or brainand no overt toxicity was observedThe only concern is that the plasma half life following oral administration may be too short for once a day dosing in relapse preventionThis can be addressed by formulation as an oral extended release formulation or by a transdermal patchwhich would also have other advantages for treatment of alcohol use disordersIntellectual property in JRas a treatment for aspects of alcohol withdrawal and the transdermal patch formulation of JRare covered by provisional applications to the USPTOThe preliminary data indicates that JRis an excellent candidate as an anti relapse medicationand the current proposal is to develop the drug further for this useThe aim is now to complete the studies required prior to submission of the drug to the FDA for consideration as an investigational new drugINDThusin the proposed studies we will complete investigation of metabolism and metabolite identification in vitroand AbsorptionDistributionMetabolismand Excretion in vivoThe studies will also include a screen for off target actions and studies on safety and toxicology in two speciesrats and non human primatesThese studies will include escalating acute dose studiesand sub chronic studiesto reflect the maintenance of patients on anti relapse medicationThe best formulation and dosing schedule will then be tested in a translational model of alcohol dependence in non human primatesJRwill be produced under GMP conditionsand production scaled up to meet requirements for future human trialsIf an IND designation is obtainedthe objective will then be to partner with a major pharmaceutical company in testing the drug in a human safety trialand then in clinical trials in alcohol dependent volunteersThe objective is to develop JRfor relapse prevention and neuroprotection to provide a pharmacotherapy that is more effective for these therapeutic targets than others currently available