Chemistry: natural resins or derivatives; peptides or proteins; – Peptides of 3 to 100 amino acid residues – Calcitonin; related peptides
Reexamination Certificate
2000-12-20
2003-09-09
Borin, Michael (Department: 1631)
Chemistry: natural resins or derivatives; peptides or proteins;
Peptides of 3 to 100 amino acid residues
Calcitonin; related peptides
C530S318000, C514S011400, C514S808000, C930S060000
Reexamination Certificate
active
06617423
ABSTRACT:
The present invention relates to calcitonins and calcitonin derivatives having a hypocalcemic effect. Calcitonins and calcitonin derivatives of this type are employed in particular in the field of the pharmaceutical industry and in the field of medicine, for example for the treatment of osteoporosis, of Paget's disease or of hypercalcemia.
Calcitonins are peptide hormones which consist of 32 amino acids. On account of their hypocalcemic effect and of the inhibition of bone destruction caused by them, they have great pharmacological importance. They are therapeutically employed for the treatment of osteoporosis, of Paget's disease or of hypercalcemia. Use is made here, in particular, of the calcitonins of man (hCt), of pig (pCt) or of ultimobranchial species, such as the salmon (sCt) or the eel (eCt).
The calcitonins or their derivatives of ultimobranchial species have a 20- to 50-fold higher activity in vivo than human calcitonin. Therefore these calcitonins are preferably employed for therapeutic purposes. The calcitonins of the ultimobranchial species differ considerably, however, in their amino acid sequence from the peptide of human calcitonin. For example, salmon calcitonin differs in 16 of the 32 amino acids from human calcitonin. Nevertheless, it is used to this day, since on account of its considerably higher activity the dosage for therapeutic purposes can be kept lower.
A disadvantage of calcitonins of ultimobranchial species, however, is that they cause an immune reaction in man on account of the amino acid differences. This high antigenicity leads to antibody formation against the particular calcitonin therapeutically employed, often even six months after the start of administration. This high antigenicity subsequently leads to secondary resistance and desensitization to the calcitonin employed. This necessitates, on the other hand, the administration of higher doses, which in turn lead to higher antibody formation and thus secondary resistance, and also to further side effects (contraindications).
Of the known calcitonins, further derivatives which are more active compared with the native form are known. For example, a replacement of three to five amino acid residues on the hydrophobic side of the potential &agr;-helical region (8-22) of hCt by leucines leads to more active calcitonin analogs. The activity of the calcitonin derivatives is in this case attributed to a close relationship between a potential amphiphilic &agr;-helical region between the amino acid residues 8 and 22 and the biological action of the molecule, on the other hand to the conformational flexibility and the spatial interactions of various molecular regions.
Apart from sCt and &agr;-aminosuberic acid-1,7-eCt, these analogs, however, up to now have no further clinical use for the treatment of the above mentioned diseases.
Since as a result of the high proteolytic degradation rate (in-vivo half-life) of the calcitonins therapeutically employed, at present comparatively high amounts have to be administered, this—as described above—in turn leading to rapid antibody formation (secondary resistance) and possible side effects (contraindications), the increase in the bioactivity or proteolysis resistance is ascribed great importance.
Conformationally stabilized analogs of hCt of this type having increased hypocalcemic action are disclosed in DE 44 31 121 A1. In this specification, hCt derivatives are described in which a 20-membered ring structure is produced by the introduction of a covalent lactam bridge between the amino acids in positions 17 and 21, for example by the amino acid in position 17 being aspartic acid and the amino acid in position 21 being lysine. These hCt analogs have an increased conformational stability and an increased hypocalcemic action.
This hypocalcemic action, however, is still not sufficient in order to make possible therapeutic use of these hCt analogs for the treatment of the diseases described above.
It is the object of the present invention to make available calcitonins or calcitonin derivatives which have an increased conformational stability and a high biological activity.
This object is achieved by the calcitonins and calcitonin derivatives as claimed in the precharacterizing clause of claim
1
in combination with its characterizing features.
REFERENCES:
patent: 44 31 121 (1996-05-01), None
“The Structure and Function of Calcitonon”, Cell Pathology, vol. 3:187-193 (1980), John C. Stevenson.
“Structural and Confirmational Requirements for Human Calcitonin Activity: Design, Synthesis, and Study of Lactam-Bridged Analogues”, J. Med. Chem. 1995, 38, 836-847, Kapurniotu and Taylor.
Bernhagen Jurgen
Brunner Herwig
Kapurniotu Afroditi
Barnes & Thornburg
Borin Michael
Fraunhofer-Gesellschaft zur Forderung der Angewandten Forschung
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