Trigriluzole for the Treatment of Cocaine Addiction

We have discovered trigriluzoleTRLZa tripeptide prodrug improved version of the market drug riluzoleRLZThe glutamic acid lowering properties of RLZ are ideally suited for the treatment of cocaineCOCaddictionand TRLZ is a major advance in delivering riluzole in vivo as validated in multiple in vivo studies in mouseratcynomolgous monkey and humansPhase I PKsafety and tolerability clinical trialTRLZ is actively transported by the peptide transporter PepTprior to peptidase mediated cleave after absorptionBecause of thisTRLZ displays higher oral bioavailability of the active principle RLZ than when RLZ is given alonea delayed Tmaxlonger half lifeless patient to patient variabilitya greatly reduced or eliminated negative food effect and lack of RLZ first pass mediated liver function abnormalitiesWe here seek to discover and validate first in class small molecule treatment to treat cocaine addictionby first conducting a comprehensive in vivo comparison of both TRLZ and RLZConventional strategies for COC addiction have primarily targeted receptorstransporters and metabolic enzymes and have also included vaccinesHoweverno strategyor putative candidatehas led to an approved medicationThis therapeutic gap exacerbates societal impacts and costs of COC addictionFor exampleCOC accounts forof emergency department visits for drug misuse andof admissions to drug abuse treatment programsandof COC addicts relapse after withdrawalChronic cocaine exposure dysregulates cellular glutamate uptake and signaling at glutamate excitatory projections onto medium spiny neurons in the nucleus accumbensNAcincluding synaptic strength and intrinsic excitabilityWe have prepared and evaluated andgtRLZ prodrugs across three generations of structural modificationsThe first generation validated our desired in vitro profilethe second established a favorable in vivo profile in multiple species but had hERG activityand the third contained the positive attributes of the previous two but without hERG activityICandgtMleading ultimately to TRLZIn Aimwe will compare the efficacy and potency of TRLZ and RLZ against relapse to COC seeking in a cueinduced self administrationSAmodel in male and female ratsThe route of administration will be i p followed by p oas we anticipate clinical use among COC addicts will conducted using oral dosingand the once daily dosing of TRLZ is one of its salient benefitscompared to RLZ at twice dailyIn Aimwe will characterize the effects of TRLZ on the reinforcing and motivational strength of COC in male and female rats maintained under a progressive ratioPRreinforcement scheduleIf this program of study yields favorable data for the use of TRLZ in the treatment COC addiction as expectedthis is recognized by experts in the field to be sufficient to quality TRLZ to advance into Phase II III human clinical trials for the treatment of COC addictiona condition for which there is currently no approved medicationA path for further development has already been identified which involves a combination of private investment and NIDA support for the required clinical trials Cocaine addiction accounts forof emergency department visits for drug misuse andof admissions to drug abuse treatment programsFurtherof COC addicts relapse after withdrawalWe have discovered trigriluzule as a prodrug of the marketed drug riluzolewith substantial clinical benefit in increasing exposure of riluzole upon oral administration and reducing or eliminating riluzole liver function abnormalities and negative food effectTrigriluzole is expected to be effective in treating cocaine addiction because it lowers glutamic acid levels in the central nervous systema key mediator promoting cocaine seeking behavior