Therapeutic agents for reducing parathyroid hormone levels
Compounds having activity for lowering parathyroid hormone levels are described. In one embodiment, the compounds are comprised of a contiguous sequence of subunits, X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 , wherein the X 1 subunit comprises a thiol-containing moiety and the distribution of charge on the X 2 -X 7 subunits provides the desired activity. Methods of using the compounds for treating hyperparathyroidism, bone disease and/or hypercalcemic disorders are also described, and in particular, methods for lowering plasma PTH and serum calcium are provided. The compounds can be used to treat subjects having, for example: primary, secondary or tertiary hyperparathyroidism; hypercalcemia of malignancy; metastatic bone disease; or osteoporosis.
1. A conjugate, comprising a peptide and a conjugating group, wherein the peptide comprises the amino acid sequence carrrar (SEQ ID NO:2), and wherein the peptide is linked to the conjugating group by a disulfide bond.
2. The conjugate of claim 1 , wherein the peptide is chemically modified at the N-terminus, the C-terminus, or both.
3. The conjugate of claim 1 , wherein the N-terminus of the peptide is chemically modified by acetylation and the C-terminus of the peptide is chemically modified by amidation.
4. The conjugate of claim 1 , wherein the conjugating group is L-Cys.
5. The conjugate of claim 1 , wherein the conjugating group is D-Cys.
6. A pharmaceutical composition comprising the conjugate according to claim 1 and a pharmaceutically acceptable excipient.
7. The pharmaceutical composition of claim 6 , wherein the conjugating group is L-Cys.
8. The pharmaceutical composition of claim 6 , wherein the conjugating group is D-Cys.
9. The pharmaceutical composition of claim 6 , wherein the peptide is chemically modified at the N-terminus, the C-terminus, or both.
10. The pharmaceutical composition of claim 6 , wherein the N-terminus of the peptide is chemically modified by acetylation and the C-terminus of the peptide is chemically modified by amidation.
11. A method of treating secondary hyperparathyroidism (SHPT) in a subject, comprising administering to the subject a therapeutically effective amount of a conjugate comprising a peptide and a conjugating group, wherein the peptide comprises the amino acid sequence carrrar (SEQ ID NO:2), and wherein the peptide is linked to the conjugating group by a disulfide bond.
12. The method of claim 11 , wherein said administering comprises administering intravenously.
13. The method of claim 11 , wherein said administering comprises administering transdermally.
14. The method of claim 11 , wherein the conjugating group is L-Cys.
15. The method of claim 11 , wherein the conjugating group is D-Cys.
16. The method of claim 11 , wherein the peptide is chemically modified at the N-terminus, the C-terminus, or both.
17. The method of claim 11 , wherein the N-terminus of the peptide is chemically modified by acetylation and the C-terminus of the peptide is chemically modified by amidation.
18. A method of decreasing parathyroid hormone levels in a subject, comprising administering to the subject an amount of a conjugate comprising a peptide and a conjugating group, wherein the peptide comprises the amino acid sequence carrrar (SEQ ID NO:2), and wherein the peptide is linked to the conjugating group by a disulfide bond.
19. The method of claim 18 , wherein said administering comprises administering intravenously.
20. The method of claim 18 , wherein said administering comprises administering transdermally.
21. The method of claim 18 , wherein the conjugating group is L-Cys.
22. The method of claim 18 , wherein the conjugating group is O-Cys.
23. The method of claim 18 , wherein the peptide is chemically modified at the N-terminus, the C-terminus, or both.
24. The method of claim 18 , wherein the N-terminus of the peptide is chemically modified by acetylation and the C-terminus of the peptide is chemically modified by amidation.
25. A method for treating a subject, comprising administering to the subject (i) a conjugate comprising a peptide and a conjugating group, wherein the peptide comprises the amino acid sequence carrrar (SEQ ID NO:2), and wherein the peptide is linked to the conjugating group by a disulfide bond and (ii) a second therapeutic agent.
26. The method of claim 25 , wherein the second therapeutic agent is vitamin D, a vitamin D analog or cinacalcet hydrochloride.
27. The method of claim 25 , wherein the conjugating group is L-Cys.
28. The method of claim 25 , wherein the conjugating group is D-Cys.
29. The method of claim 25 , wherein the peptide is chemically modified at the N-terminus, the C-terminus, or both.
30. The method of claim 25 , wherein the N-terminus of the peptide is chemically modified by acetylation and the C-terminus of the peptide is chemically modified by amidation.