Synthetic peptide amide dimers
The invention relates to synthetic peptide amide ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P 450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure: Pharmaceutical compositions containing these compounds are useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions. Such treatable pain includes visceral pain, neuropathic pain and hyperalgesia. Inflammation associated with conditions such as IBD and IBS, ocular and otic inflammation, other disorders and conditions such as pruritis, edema, hyponatremia, hypokalemia, ileus, tussis and glaucoma are treatable or preventable with the pharmaceutical compositions of the invention.
1. A synthetic peptide amide dimer having the formula:
or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, acid salt hydrate, or N-oxide thereof,
wherein
each Xaa 1 is independently selected from the group consisting of (A)(A′)D-Phe, (A)(A′)(α-Me)D-Phe, D-Tyr, D-Tic, D-tert-leucine, D-neopentylglycine, D-phenylglycine, D-homophenylalanine, and β-(E)D-Ala, wherein each (A) and each (A′) are phenyl ring substituents independently selected from the group consisting of —H, —F, —Cl, —NO 2 , —CH 3 , —CF 3 , —CN, —CONH 2 , and wherein each (E) is independently selected from the group consisting of cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, thienyl and thiazolyl;
each Xaa 2 is independently selected from the group consisting of (A)(A′)D-Phe, (A)(A′)(α-Me)D-Phe, D-1NaI, D-2NaI, D-Tyr, (E)D-Ala, and D-Trp;
each Xaa 3 is independently selected from the group consisting of D-Nle, D-Phe, (E)D-Ala, D-Leu, (α-Me)D-Leu, D-Hle, D-Val, and D-Met;
each Xaa 4 is independently selected from the group consisting of (B) 2 D-Arg, (B) 2 D-Nar, (B) 2 D-Har, ζ-Dap, ε-(B)D-Lys, ε-(B) 2 -D-Lys, D-Amf, amidino-D-Amf, γ-(B) 2 D-Dbu, δ-(B) 2 α-(B′)D-Orn, D-2-amino-3(4-piperidyl)propionic acid, D-2-amino-3(2-aminopyrrolidyl)propionic acid, D-α-amino-β-amidino-propionic acid, α-amino-4-piperidineacetic acid, cis-α,4-diaminocyclohexane acetic acid, trans-α,4-diaminocyclohexaneacetic acid, cis-α-amino-4-methyl-aminocyclo-hexane acetic acid, trans-α-amino-4-methylaminocyclohexane acetic acid, α-amino-1-amidino-4-piperidineacetic acid, cis-α-amino-4-guanidino-cyclohexane acetic acid, and trans-α-amino-4-guanidinocyclohexane acetic acid, wherein each (B) is independently selected from the group consisting of —H and C 1 -C 4 alkyl, and (B′) is —H or (α-Me), and p is zero or 1;
q is zero or 1;
r is zero or 1;
s is zero or 1;
p and t are each independently zero or 1, provided that at least one of q, r, s and t is 1; and
wherein either
A. (i) L is a linker selected from the group consisting of ε-D-Lys, ε-Lys, δ-D-Orn, δ-Orn, γ-aminobutyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxaoctanoic acid, 4-amino-4-carboxylic piperidine, and (D-Lys-Gly lactam) 2 , and
(ii) the moieties Xaa 1 -Xaa 2 -Xaa 3 -(Xaa 4 ) p and (Xaa 1 ) q -(Xaa 1 ) r -(Xaa 3 ) s -(Xaa 4 ) t are different from one another;
or
B. L is a linker selected from the group consisting of γ-aminobutyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxaoctanoic acid, 4-amino-4-carboxylic piperidine, and (D-Lys-Gly lactam) 2 .
2. The synthetic peptide amide dimer of claim 1 wherein p, q, r, s and t are each 1.
3. The synthetic peptide amide of claim 1 wherein p, r, s and t are each 1 and q is 0.
4. The synthetic peptide amide dimer of claim 1 wherein p, s and t are each 1 and q and r are each 0.
5. The synthetic peptide amide dimer of claim 1 wherein p and t are each 1 and q, r and s are each 0.
6. The synthetic peptide amide dimer of claim 1 wherein q, r, s and t are each 1 and p is 0.
7. The synthetic peptide amide dimer of claim 1 wherein L is a linker selected from the group consisting of ε-D-Lys, ε-Lys, δ-D-Orn, δ-Orn, 4-amino-4-carboxylic piperidine and (D-Lys-Gly lactam) 2 .
8. The synthetic peptide amide dimer of claim 7 wherein L is ε-Lys or ε-D-Lys.
9. The synthetic peptide amide dimer of claim 1 wherein L is (D-Lys-Gly lactam) 2 .
10. The synthetic peptide amide dimer of claim 1 wherein L is 4-amino-4-carboxylic piperidine.
11. The synthetic peptide amide dimer of claim 1 wherein Xaa 1 -Xaa 2 - is (A)(A′)D-Phe-(A)(A′)D-Phe-.
12. The synthetic peptide amide dimer of claim 11 wherein Xaa 1 -Xaa 2 - is D-Phe-D-Phe-.
13. The synthetic peptide amide dimer of claim 12 wherein -Xaa 3 -(Xaa 4 ) p is -D-Leu-(D-Orn) p .
14. The synthetic peptide amide dimer of claim 13 wherein L is ε-Lys, ε-D-Lys, (D-Lys-GlyLactam) 2 , or (Lys-Gly Lactam) 2 .
15. The synthetic peptide amide dimer of claim 14 wherein p is 1.
16. The synthetic peptide amide dimer of claim 1 , having a structure selected from the group consisting of:
17. The synthetic peptide amide dimer of claim 1 wherein the moieties Xaa 1 -Xaa 2 -Xaa 3 -(Xaa 4 ) p and (Xaa 1 ) q -(Xaa 2 ) r -(Xaa 3 ) s -(Xaa 4 ) t are different from one another.
18. The synthetic peptide amide dimer of claim 17 wherein p, q, r, s and t are each 1.
19. The synthetic peptide amide dimer of claim 1 wherein L is a linker selected from the group consisting of γ-aminobutyric acid, 8-aminooctanoic acid, 11-amino-undecanoic acid, 8-amino-3,6-dioxaoctanoic acid, 4-amino-4-carboxylic piperidine, and (D-Lys-Gly lactam) 2 .
20. The synthetic peptide amide dimer of claim 19 wherein p, q, r, s and t are each 1.
21. The synthetic peptide amide dimer according to claim 19 , having an EC 50 of less than about 500 nM for a kappa opioid receptor.
22. A pharmaceutical composition comprising the synthetic peptide amide dimer according to claim 1 and a pharmaceutically acceptable excipient or carrier.
23. A synthetic peptide amide dimer having the formula:
or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, acid salt hydrate, or N-oxide thereof