Treatment of addiction and impulse-control disorders using PDE7 inhibitors
Inventors
Demopulos, Gregory A. • Gaitanaris, George A. • Ciccocioppo, Roberto
Assignees
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Publication Number
US-11464785-B2
Publication Date
2022-10-11
Expiration Date
Abstract
This disclosure is directed to treatment of addictions and primary impulse-control disorders using phosphodiesterase 7 (PDE7) inhibitors, alone or in combination with other therapeutic agents.
Core Innovation
The disclosed method treats nicotine addiction by determining that a subject has an addiction to nicotine and administering an amount of a selective phosphodiesterase 7 (PDE7) inhibitor effective to reduce the subject's self-administration of nicotine. The inhibitory agent is a compound of formula 6, or a pharmaceutically acceptable salt or solvate thereof, which meets a specified selectivity criterion against other PDE enzyme families. Selectivity requires that the lesser of the IC50 for inhibiting PDE7A activity and the IC50 for inhibiting PDE7B activity is less than one-tenth the IC50 for inhibiting any other PDE enzyme from the PDE1-6 and PDE8-11 families.
The description identifies candidate inhibitor chemotypes encompassing formulae 6A-6H, imidazopyridine, quinazoline, spiroquinazolinone, pyrimidine-thiazole, pyrrole, phenothiazine, and isoxazole scaffolds, as well as formulations for intravenous administration. In animal models, selective PDE7 inhibitors reduce nicotine self-administration, motivation, cue- and stress-induced reinstatement, and nicotine-evoked dopamine increases. Food self-administration controls and basal dopamine levels remain largely unaffected by the administration of the selective inhibitor compounds.
Claims Coverage
The claims identify one independent claim directed to treating nicotine addiction comprising four inventive features.
Determining nicotine addiction
The method determines that a subject has an addiction to nicotine.
Reducing nicotine self-administration
The method administers an amount of a PDE7 inhibitor effective for the reduction of self-administration of nicotine by the subject.
Selective PDE7 inhibition
The PDE7 inhibitory agent is selective such that the lesser of its IC50 for inhibiting PDE7A activity and its IC50 for inhibiting PDE7B activity is less than one-tenth its IC50 for inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families.
Formula 6 inhibitor compound
The PDE7 inhibitory agent is a compound of formula 6, or a pharmaceutically acceptable salt or solvate thereof, with substituent groups specified in the claim.
The independent claim combines determining nicotine addiction, administering an effective amount of a selective PDE7 inhibitor to reduce nicotine self-administration, and utilizing a specified formula 6 compound limitation.
Stated Advantages
The administered PDE7 inhibitor is effective for reducing self-administration of nicotine by the subject.
The inhibitor reduces relapse and cue- or stress-induced reinstatement of nicotine use.
Food self-administration controls and food-trained extinction controls remain largely unaffected, demonstrating selectivity for drug-related responding.
The inhibitor attenuates nicotine-evoked dopamine increases while leaving basal dopamine levels broadly unchanged.
Documented Applications
Treating nicotine addiction and reducing nicotine self-administration in a subject.
Reducing cue- and stress-induced reinstatement of nicotine use after extinction.
Formulating and administering selective PDE7 inhibitors alone or in combination with other agents, including intravenous pharmaceutical compositions.
Evaluating PDE7 inhibitors in experimental contexts involving nicotine-seeking behavior, cocaine self-administration, stress-induced binge eating, and food seeking.
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