Novel Modafinil Analogs as Cocaine Pharmacotherapies

SUMMARYCocaine addiction is a serious neuropsychological condition with profound consequences on both an individual and societyHoweverat present there are no FDA approved pharmaceutical treatments for cocaine addictionOne potential solution is to develop inhibitors at biogenic amine transportersespecially the dopamine transporterDATthat are structurally dissimilar to cocaine and could potentially bind to different sites compared to cocaine within DATSuch inhibitors may have the ability to block some of cocaineandapos s behavioral actions without producing some of the major undesirable effectse gmotor stimulationhigh reinforcement activityproduced by cocaine and other cocaine like DAT inhibitorsModafinilProvigila weak DAT inhibitor that is used clinicallyat high dosesfor treatment of narcolepsyhas been tested in clinical trials for cocaine addiction treatment with mixed resultsIn particularthe weak potencylow efficacy and unfavorable side effects limit the potential utility of modafinil itself as a cocaine pharmacotherapyNewly patented modafinil analogs developed by DrAmy Newmanandapos s lab at the NIDA Intramural Research ProgramIRPare more potent than modafinil at DATand preliminary behavioral data show that these analogs block cocaine self administration in rats without producing significant reinforcement or motor stimulation on their ownAfter winning a national competition sponsored by the NIH to create a company around a specific NIH inventionEncepHeal Therapeutics has obtained an exclusive license to this technology and is prepared to further develop and commercialize it as potential pharmacotherapies to treat cocaine addictionThe proposed research in this Phase I SBIR project will focus on characterizing drug candidates from an in licensed library of novel modafinil analogs produced by DrNewman at the NIDA IRPThese studies will achieve the followingDetermine in vitro metabolism of selected modafinil analogs in liver microsomesCYP inductionand cardiac safetyDetermine in vitro radioligand binding affinities at human biogenic amine transportershDAThSERTand hNETand perform preliminary quantification of pharmacokineticPKproperties after in vivo administration of analogs in ratsExamine blockade of cocaine self administration in rats on progressive ratio schedulesand intrinsic reinforcement properties in rats on a fixed ratio drug discrimination assayAll of the data generated by this SBIR project will be combined with complementary data from the NIDA IRP to provide a complete preclinical description of lead drug candidate sto be commercialized by EncepHeal for further development as a medication agent for cocaine addictionThese compiled data will assist EncepHeal Therapeutics in choosing a single lead compound for Phase II evaluation of efficacy in non human primatesother IND enabling testsand future commercializationNARRATIVECocaine addiction is a serious medical and social problemyet there are no medications approved by the FDA to treat cocaine addictsModafinilProvigilcurrently marketed to treat sleep disordershas been suggested as a potential treatment agent for cocaine addictionbut its weak potency has limited its usefulness in the clinicThis project will develop novel modafinil analogs as medications to reduce craving for cocaine in human addicts