Details for Patent: 9,567,370
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Title: | Therapeutic agents for reducing parathyroid hormone levels |
Abstract: | Compounds having activity for lowering parathyroid hormone levels are described. In one embodiment, the compounds are comprised of a contiguous sequence of subunits, X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7, wherein the X.sub.1 subunit comprises a thiol-containing moiety and the distribution of charge on the X.sub.2-X.sub.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. |
Inventor(s): | Karim; Felix (Walnut Creek, CA), Baruch; Amos (San Francisco, CA), Maclean; Derek (Los Altos, CA), Das; Kanad (San Francisco, CA), Yin; Qun (Palo Alto, CA) |
Assignee: | KAI PHARMACEUTICALS, INC. (South San Francisco, CA) |
Filing Date: | Mar 04, 2015 |
Application Number: | 14/639,020 |
Claims: | 1. A compound comprising a peptide 8 to 15 amino acids in length comprising the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7, wherein: X.sub.1 is L-cysteine or D-cysteine, X.sub.2 is D-alanine or D-arginine, X.sub.3 is D-arginine, X.sub.4 is D-alanine or D-arginine, X.sub.5 is D-arginine, X.sub.6 is D-alanine, and X.sub.7 is D-arginine. 2. The compound of claim 1, wherein the peptide is 8 to 11 amino acids in length. 3. The compound of claim 1, wherein the peptide comprises the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7, wherein: X.sub.2 is D-alanine, X.sub.3 is D-arginine, X.sub.4 is D-arginine, X.sub.5 is D-arginine, X.sub.6 is D-alanine, and X.sub.7 is D-arginine. 4. The compound of claim 1, wherein the N-terminus of the peptide is acetylated. 5. The compound of claim 1, wherein the C-terminus of the peptide is amidated. 6. The compound of claim 1, wherein the N-terminus of the peptide is acetylated and the C-terminus of the peptide is amidated. 7. The compound of claim 1, wherein X.sub.1 is conjugated to a conjugating group via a disulfide bond. 8. The compound of claim 7, wherein the conjugating group is selected from the group consisting of cysteine, homocysteine, glutathione, pegylated cysteine and a thiol-containing polypeptide. 9. The compound of claim 7, wherein the conjugating group is L-cysteine. 10. The compound of claim 7, wherein the conjugating group is D-cysteine. 11. The compound of claim 3, wherein the N-terminus of the peptide is acetylated. 12. The compound of claim 3, wherein the C-terminus of the peptide is amidated. 13. The compound of claim 3, wherein the N-terminus of the peptide is acetylated and the C-terminus of the peptide is amidated. 14. The compound of claim 3, wherein X.sub.1 is conjugated to a conjugating group via a disulfide bond. 15. The compound of claim 14, wherein the conjugating group is selected from the group consisting of cysteine, homocysteine, glutathione, pegylated cysteine and a thiol-containing polypeptide. 16. The compound of claim 14, wherein the conjugating group is L-cysteine. 17. The compound of claim 14, wherein the conjugating group is D-cysteine. 18. A pharmaceutical composition comprising the compound of claim 1. 19. A pharmaceutical composition comprising the compound of claim 3. 20. A method of treating secondary hyperparathyroidism (SHPT) in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1. 21. The method of claim 20, wherein the subject is suffering from chronic kidney disease. 22. The method according to claim 20, wherein the administering is intravenous. 23. A method of treating secondary hyperparathyroidism (SHPT) in a subject, comprising administering to the subject a therapeutically effective amount of the compound according to claim 3. 24. The method of claim 23, wherein the subject is suffering from chronic kidney disease. 25. The method according to claim 23, wherein the administering is intravenous. 26. The compound of claim 2, wherein the peptide comprises the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7, wherein: X.sub.2 is D-alanine, X.sub.3 is D-arginine, X.sub.4 is D-arginine, X.sub.5 is D-arginine, X.sub.6 is D-alanine, and X.sub.7 is D-arginine. 27. The compound of claim 1, wherein the peptide comprises the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7, wherein: X.sub.2 is D-arginine, X.sub.3 is D-arginine, X.sub.4 is D-alanine, X.sub.5 is D-arginine, X.sub.6 is D-alanine, and X.sub.7 is D-arginine. 28. The compound of claim 2, wherein the peptide comprises the amino acid sequence X.sub.1-X.sub.2-X.sub.3-X.sub.4-X.sub.5-X.sub.6-X.sub.7, wherein: X.sub.2 is D-arginine, X.sub.3 is D-arginine, X.sub.4 is D-alanine, X.sub.5 is D-arginine, X.sub.6 is D-alanine, and X.sub.7 is D-arginine. |