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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: 4U44AA026126-03
Agency Tracking Number: U44AA026126
Amount: $3,415,022.00
Phase: Phase II
Program: SBIR
Solicitation Topic Code: 150
Solicitation Number: PAR15-154
Solicitation Year: 2015
Award Year: 2021
Award Start Date (Proposal Award Date): 2021-09-01
Award End Date (Contract End Date): 2024-08-31
Small Business Information
UK-ASTECC 145 Graham Avenue
Lexington, KY 40506-0286
United States
DUNS: 196165877
HUBZone Owned: No
Woman Owned: No
Socially and Economically Disadvantaged: No
Principal Investigator
 (859) 257-1127
Business Contact
Phone: (502) 583-7454
Research Institution

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 rt70%). 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 (rats and
non-human primates). These studies will include escalating acute dose studies, and sub-chronic studies (to
reflect the maintenance of patients on anti-relapse medication). The best formulation and dosing schedule will
then be tested in a translational model of alcohol dependence in non-human primates. 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.

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

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