Treatment of addiction and impulse-control disorders using PDE7 inhibitors
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.
1. A method of treating an addiction to nicotine, comprising:
determining that a subject has an addiction to nicotine; and
administering to the subject an amount of an inhibitor of a phosphodiesterase 7 (PDE7) effective for the reduction of self administration of nicotine by the subject, wherein the PDE7 inhibitory agent is a selective PDE7 inhibitor for which the lesser of the IC 50 for inhibiting PDE7A activity and the IC 50 for inhibiting PDE7B activity is less than one-tenth the IC 50 that the agent has for inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families, and wherein the PDE7 inhibitory agent is a compound of formula 6:
or a pharmaceutically acceptable salt or a solvate thereof, wherein:
R 1 is substituted or unsubstituted C3-8 alkyl group, substituted or unsubstituted cycloalkyl group, or substituted or unsubstituted heterocycloalkyl group;
R 2 is a hydrogen atom or substituted or unsubstituted C1-3 alkyl group;
R 3 is a hydrogen atom, substituted or unsubstituted C1-3 alkyl group, or a halogen atom; and
R 4 is substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, or a group CONR 5 R 6 , or CO 2 R 7 ,
wherein R 5 and R 6 are, same or different from each other, a hydrogen atom; C1-6 alkyl group which may be substituted by a halogen atom, substituted or unsubstituted aryl group, substituted or unsubstituted heteroaryl group, substituted or unsubstituted heterocycloalkyl group, substituted or unsubstituted cycloalkyl group, a group NR 7 COR 8 , COR 8 , NR 9 R 10 ; substituted or unsubstituted cycloalkyl group; substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted aryl group; substituted or unsubstituted heteroaryl group; or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5 and R 6 ;
wherein R 7 is a hydrogen atom or substituted or unsubstituted C1-3 alkyl group;
wherein R 8 is substituted or unsubstituted heterocycloalkyl group, or a group OH, OR 7 , or NR 9 R 10 ; and
wherein R 9 and R 10 are, same or different from each other, a hydrogen atom; substituted or unsubstituted C1-3 alkyl group, substituted or unsubstituted heterocycloalkyl group; substituted or unsubstituted acyl; a group SO 2 R 7 , or substituted or unsubstituted heterocycloalkyl group in which the ring is formed together with the nitrogen atom binding R 5 and R 6 .
2. The method of claim 1 , wherein the amount of the PDE7 inhibitor administered is effective to accelerate extinction of use of nicotine by the subject.
3. The method of claim 1 , further comprising, after determining that the subject has an addiction to nicotine and prior to administering the PDE7 inhibitor:
determining that the subject has gone through a period of extinction of use of nicotine; and
determining that the subject is experiencing stress-induced reinstatement of use of nicotine,
wherein the amount of the PDE7 inhibitor is effective to reduce reinstatement of use of nicotine by the subject.
4. The method of claim 1 , wherein the PDE7 inhibitory agent has an IC 50 for inhibiting PDE7A and/or PDE7B activity of less than about 1 μM.
5. The method of claim 1 , wherein the PDE7 inhibitory agent has an IC 50 for inhibiting PDE7A and/or PDE7B activity of less than about 100 nM.
6. The method of claim 1 , wherein the PDE7 inhibitory agent is a highly selective PDE7 inhibitor for which the lesser of the IC 50 for inhibiting PDE7A activity and the IC 50 for inhibiting PDE7B activity is less than one-fiftieth the IC 50 that the agent has for inhibiting the activity of any other PDE enzyme from the PDE1-6 and PDE8-11 enzyme families.
7. The method of claim 1 , wherein the PDE7 inhibitory agent has a molecular weight of less than about 450 g/mole.
8. The method of claim 1 , wherein the PDE7 inhibitory agent is able to cross the blood/brain barrier.
9. The method of claim 1 , wherein the PDE7 inhibitory agent of formula 6 is a member selected from the group consisting of formula 6A, formula 6B, formula 6C, formula 6D, formula 6E, formula 6F, formula 6G, and formula 6H: