Parathyroid hormone analogues for the treatment of osteoporosis

Details Parathyroid hormone analogues for the treatment of osteoporosis Parathyroid hormone analogues for the treatment of osteoporosis

C - Chemistry, Metallurgy

07

K

C07K 14/635 (2006.01) A61K 38/17 (2006.01) A61P 5/18 (2006.01) C07K 7/02 (2006.01) A61K 38/00 (2006.01)

Patent

CA 2384341

The invention disclosed relates to analogues of human parathyroid hormone (hPTH) which have increased activites in bone restoration, and increased bioavailabilities. 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.

Analogues de l'hormone parathyroïdienne humaine (PTH) qui possèdent une activité de reconstitution osseuse et une biodisponibilité accrues. Les analogues décrits sont soit des analogues cycliques simples (1-28) ou (1-29), soit des analogues cycliques doubles (1-28) à (1-31). Les analogues cycliques simples sont cyclisés entre les paires d'acides aminés R22 et R26. Les analogues cycliques doubles sont cyclisés entre les paires d'acides aminés 13 et 17, et 22 et 26. Diverses substitutions des restes naturels par d'autres acides aminés sont également décrites. Par exemple, le reste naturel Lys27 peut être substitué par Leu. Typiquement, ces nouveaux analogues possèdent des capacités améliorées pour stimuler l'activité de l'adényl cyclase dans des cellules d'ostéosarcome murines, et présentent une activité améliorée en matière de reconstitution osseuse constatée sur la rate ayant subi l'ablation des ovaires.

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