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 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.

We claim: 
     
         1 . A compound comprising the formula:
   X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7      wherein
 X 1  is an amino acid comprising a thiol-containing group, D-penicillamine, d-homocysteine or mercaptopropionic acid; 
 X 2 , X 3 , X 4 , X 5 , X 5 , and X 7  are each D-arginine. 
   
     
     
         2 . The compound of  claim 1 , wherein X 1  is an amino acid comprising a thiol-containing group is selected from L-cysteine and D-cysteine. 
     
     
         3 . The compound of  claim 1  or  claim 2 , wherein the compound is chemically modified at the N-terminus, the C-terminus or both. 
     
     
         4 . The compound of any one of  claims 1 - 3 , wherein the N-terminus of the compound is acetylated and the C-terminus of the peptide is amidated. 
     
     
         5 . The compound of any one of  claims 1 - 4 , wherein the compound is Ac-crrrrrr-NH 2  (SEQ ID NO: 6). 
     
     
         6 . The compound of any one of  claims 1 - 4 , wherein the compound is Ac-beta alanine-rrrrrr-NH 2  (SEQ ID NO: 30). 
     
     
         7 . The compound of any one of  claims 1 - 4 , wherein the compound is mercaptopropionic acid-rrrrrr-NH 2  (SEQ ID NO: 31). 
     
     
         8 . The compound of any one of  claims 1 - 4 , wherein the compound is Ac-d-homocysteine-rrrrrr-NH 2  (SEQ ID NO: 32). 
     
     
         9 . The compound of any one of  claims 1 - 4 , wherein the compound is Ac-D-penicillamin-rrrrrr-NH 2  (SEQ ID NO: 33). 
     
     
         10 . A composition comprising the compound of any one of  claims 1 - 9  and a pharmaceutically acceptable excipient. 
     
     
         11 . A composition comprising a compound according to any one of  claim 10 , for use in the treatment of a subject suffering from hyperparathyroidism or a hypercalcemic disorder.