National Research Council of Canada

Gordon E Willick

James F Whitfield

Witold A Neugebauer

Paul Morley

Jean-Rene Barbier

Virginia J Ross

Wing L Sung

Witold Surewicz

Jean-Ren&eacute; Barbier

This invention describes analogues of human parathyroid hormone which have increased activities in bone restoration, and increased bioavailability. The peptides described are derivatives of hPTH-(1-31) which are cyclized for example, by formation of lactams between either Glu and Lys or Lys and Asp . In addition, the natural Lys may be substituted by either a Leu or other hydrophobic residues, such as Ile, norleucine, Met, Val, Ala, Trp, or Phe. Typically, these analogues have enhanced abilities to stimulate adenylyl cyclase in rat osteosarcoma cells, and show increased activities in bone restoration, using the ovariectomized rat model. The analogues also show enhanced activities and bioavailabilities, as demonstrated by their hypotensive effects in the rat. An assay which correlates hypotensive activity with osteogenic activity is also described.

Parathyroid hormone analogues for the treatment of osteoporosis

The invention disclosed relates to analogues of human parathyroid hormoneh(PTH) which have increased activities in bone restoration, and increased bioavailablities. The analogues described are either single cyclic (1-28) or (1-29) analogues, or double cyclic (1-28) to (1-31) analogues. The single cyclic analogues are cyclised between amino acid pairs R22 and R26. The double cyclic analogues are cyclised between amino acid pairs 13 and 17, and 22 and 26. Various substitutions of the natural residues for other amino acids are also described. For example, the natural Lys27 residue may be substituted by Leu. Typically, these novel analogues have enhanced abilities to stimulate adenyl cyclase activity in rat osteosarcoma cells, and show increased activities in bone restoration using the ovariectomized rat model.

This invention describes analogues of human parathyroid hormone which have increased activities in bone restoration, and increased bioavailabilities. The peptides described are derivatives of hPTH-(1-31) which are cyclized for example, by formation of lactams between either Glu.sup.22 and Lys.sup.26 or Lys.sup.26 and Asp.sup.30. In addition, the natural Lys.sup.27 may be substituted by either a Leu or other hydrophobic residues, such as Ile, norleucine, Met, Val, Ala, Trp, or Phe. Typically, these analogues have enhanced abilities to stimulate adenylyl cyclase in rat osteosarcoma cells, and show increased activities in bone restoration, using the ovariectomized rat model. The analogues also show enhanced activities and bioavailabilities, as demonstrated by their hypotensive effects in the rat. An assay which correlates hypotensive activity with osteogenic activity is also described.

This invention describes analogs of human parathyroid hormone which have increased activities in bone restoration, and increased bioavailabilities. The peptides described are derivatives of hPTH-(1-31) which have lactams formed for example, between either Glu.sup.22 and Lys.sup.26 or Lys.sup.26 and Asp.sup.30. In addition, the natural Lys.sup.27 may be substituted by either a Leu or other hydrophobic residues, such as Ile, norleucine, Met, Val, Ala, Trp, or Phe. Typically, these analogs have enhanced abilities to stimulate adenylyl cyclase in rat osteosarcoma cells, and show increased activities in bone restoration, using the ovariectomized rat model. The analogs also show enhanced activities and bioavailabilities, as demonstrated by their hypotensive effects in the rat.

Certain analogues of human parathyroid hormone (hPTH) have been found to be effective for the treatment of osteoporosis, while showing decreased side effects. Analogues showing this effect include all sequences from hPTH-(1-28)-NH.sub.2 to hPTH-(1-31)-NH.sub.2 and all sequences from [Leu.sup.27 ]-hPTH-(1-28)-NH.sub.2 to [Leu.sup.27 ]-hPTH-(1-33)-NH.sub.2. Also included are cyclic analogues cyclo(Lys.sup.26 -Asp.sup.30) [Leu.sup.27 ]-hPTH-(1-34)NH.sub.2 and cyclo (Lys.sup.27 -Asp.sup.30 )-hPTH-(1-34)-NH.sub.2. Analogues in the form of the carboxyl terminal amide are particularly effective.

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Orleans, Canada

Gordon E Willick