Neuropeptide S receptor (NPSR) agonists
Neuropeptide S receptor agonists are provided. The NPS agonists include peptidomimetic analogs exhibiting affinity for and activity at the neuropeptide S receptor. The molecules may be useful in the treatment of disorders, syndromes and conditions mediated by modulation of the neuropeptide S receptor such as substance abuse, narcolepsy, insomnia, obesity, cognitive decline, dementia, Alzheimer's disease, panic disorder, generalized anxiety, PTSD, phobias, schizophrenia and as supportive medication during any kind of cessation program in cognitive behavioral therapy, such as drug addiction, eating disorders and gambling.
1. A compound of Formula I:
wherein:
R 1 is selected from phenyl, benzyl, benzyloxy, phenethyl, C 1 -C 4 alkylcycloalkyl, benzamido, polycyclic heterocycle, or branched or unbranched C 1 -C 6 alkyl;
R 2 is selected from benzyl;
R 3 is H, benzyl, or lysine side chain;
R 4 is
(a) a five membered saturated ring substituted with one C(O)NH 2 group;
(b) a six membered saturated or aromatic ring substituted with one C(O)NH 2 group,
(c) C 1 -C 3 amidoalkyl; and
R 5 is H or C 1 -C 6 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein:
R 1 is phenethyl;
R 2 is benzyl;
R 4 is a six membered saturated ring substituted with one C(O)NH 2 group, and
R 3 and R 5 are each H.
3. The compound of claim 1 , wherein R 1 is phenyl or benzyl, and R 2 is benzyl.
4. The compound of claim 1 , wherein R 1 is benzamido, R 2 is benzyl, R 4 is a six membered saturated ring substituted with one C(O)NH 2 , and R 5 is methyl.
5. The compound of claim 1 , wherein
R 1 is phenethyl, and
R 4 is a six membered saturated ring substituted with one C(O)NH 2 .
6. The compound of claim 1 , wherein
R 1 phenethyl, is
R 2 benzyl, is
R 3 is H or lysine side chain, and
R 4 is
(a) a five membered saturated ring substituted with one C(O)NH 2 group, or
(b) a six membered saturated or aromatic ring substituted with one C(O)NH 2 group.
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
8. The compound of claim 1 , wherein R 1 is benzamido, R 2 is benzyl, R 4 is C 1 -C 3 amidoalkyl, and R 5 is H or benzyl.
9. The compound of claim 8 , wherein R 4 is —CH(CH 2 )CH 2 C(O)NH 2 or —CH(Ph)-CH—C(O)NH 2 .
10. The compound of claim 1 , wherein R 1 is C 1 -C 4 -alkylcycloalkyl, or branched or unbranched C 1 -C 6 -alkyl, R 2 is benzyl, R 4 is a six membered saturated ring substituted with one C(O)NH 21 and R 3 and R 5 are H.
11. The compound of claim 10 , wherein R 1 is CH 2 CH 2 -cyclohexyl or isopentyl.
12. A method for treating a subject having a condition or disorder where modulation of neuropeptide S receptor activity is of therapeutic benefit, wherein such disorder or condition is selected from one or more of the group consisting of substance abuse, narcolepsy, insomnia, obesity, cognitive decline, dementia, Alzheimer's disease, panic disorder, generalized anxiety, PTSD, phobia, and schizophrenia, comprising administering to said subject in need thereof, a therapeutically effective amount of a compound according to claim 1 .
13. The method of claim 12 , further comprising administering an effective amount of a second active agent.
14. The compound selected from Formula II:
wherein
R 1′ is phenyl;
R 2′ is benzyl;
A, A′ and A″ are independently selected from —NH— or —O—, provided that at least one of A, A′ and A″ is —O—;
R 3′ is H, benzyl or lysine side chain; and
R 4′ is a five membered saturated ring substituted with one C(O)NH 2 group or a six membered saturated or aromatic ring substituted with one C(O)NH 2 group;
or a pharmaceutically acceptable salt thereof.
15. The compound of claim 14 , wherein R 4′ is a six membered saturated ring substituted with one C(O)NH 2 group.
16. A pharmaceutical composition comprising a compound according to claim 14 and a pharmaceutically acceptable carrier.
17. A compound:
or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound according to claim 17 and a pharmaceutically acceptable carrier.
19. A compound:
or a pharmaceutically acceptable salt thereof.
20. A pharmaceutical composition comprising a compound according to claim 19 and a pharmaceutically acceptable carrier.
21. A compound:
or a pharmaceutically acceptable salt thereof.
22. A pharmaceutical composition comprising a compound according to claim 21 and a pharmaceutically acceptable carrier.