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

Award Information
Agency: Department of Health and Human Services
Branch: National Institutes of Health
Contract: 1U44AA026126-01
Agency Tracking Number: U44AA026126
Amount: $1,467,135.00
Phase: Phase I
Program: SBIR
Solicitation Topic Code: 150
Solicitation Number: PAR15-154
Timeline
Solicitation Year: 2015
Award Year: 2017
Award Start Date (Proposal Award Date): 2017-08-25
Award End Date (Contract End Date): 2022-07-31
Small Business Information
KTRDC-UK 1401 UNVERSITY DR
Lexington, KY 40546-0001
United States
DUNS: 196165877
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 JOHN LITTLETON
 (859) 255-6757
 jlittlet@uky.edu
Business Contact
 DAVID GIBBS
Phone: (502) 583-7454
Email: dgibbs@blacksheepllc.com
Research Institution
N/A
Abstract

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

* Information listed above is at the time of submission. *

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