Calcitonin derivatives

Details Calcitonin derivatives Calcitonin derivatives

1990-12-21

2000-10-03

MacMillan, Keith D.

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

Calcitonin; related peptides

514 12, 514808, 530324, 530325, 530318, 530317, C07K 1700

Patent

active

061275190

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
The present invention relates to a novel, physiologically active family of peptides effective for the treatment of diseases caused by abnormal calcium metabolism in the body, such as hypercalcemia, Paget's Disease of bone, and osteoporosis.
2. Description of the Related Art
Estrogens, vitamin D, calcium salts, and calcitonin have been administered for the treatment of hypercalcemia, Paget's Disease of bone, and osteoporosis, but are defective in that the object is limited or the effect is not clear.
Calcitonin is a single-chain polypeptide hormone consisting of 32 amino acids, which occurs in nature and is secreted from the thyroid gland in mammals and from the ultimobranchial gland in fish, and birds. The amino acid composition or sequence differs to a large extent among the different species, but the physiological activity in blood is substantially the same there among.


SUMMARY OF THE INVENTION

Accordingly, the present inventors carried out research into the development of a calcium metabolism-regulating agent capable of treating hypercalcemia, Paget's Disease of bone, and osteoporosis, and to this end, synthesized novel peptides and examined the physiological activities thereof. As a result, it was found that the novel peptides described below have a very high activity of lowering the level of blood calcium.
More specifically, in accordance with one aspect of the present invention, there is provided a novel physiologically active peptide (hereinafter referred to as "the peptide of the present invention") having the following amino acid sequence (presented in the sequence listing as SEQ ID NO:1 thru SEQ ID NO:53):


CH.sub.2 ------------S------------S--------------CH.sub.2 .vertline. .vertline. R--CH--CO-Gly-Asn-Leu-X1--NH--CH--CO--X2-Leu-Gly-Lys-Leu- Ser-Gln-X3-Leu-His-Lys-X4-Tyr-Pro-Gln-Thr-Ala-Ile- Gly-X5-Pro-NH.sub.2 - CH.sub.3 CH.sub.3 .vertline. .vertline. R--CH--CO-Gly-Asn-Leu-X1--NH--CH--CO--X2-Leu-Gly-Lys-Leu- Ser-Gln-X3-Leu-His-Lys-X4-Tyr-Pro-Gln-Thr-Ala-Ile- Gly-X5-Pro-NH.sub.2 - CH.sub.2 ----------CH.sub.2 ----------CH.sub.2 ------------CH.sub.2 .vertline. .vertline. CH.sub.2 --CO-Gly-Asn-Leu-X1--NH--CH--CO--X2-Leu-Gly-Lys-Leu- Ser-Gln-X3-Leu-His-Lys-X4-Tyr-Pro-Gln-Thr-Ala-Ile- Gly-X5-Pro-NH.sub.2 - (CH.sub.2)n.sub.1 ----X6----------(CH.sub.2)n.sub.2 .vertline. .vertline. R--CH--CO------X7------NH--CH--CO--X8 .alpha.-aminolactic acid, calcitonin, or a substitution, deletion or addition derivative thereof, having 0 to 6 amino acids, calcitonin, or a substitution, deletion or addition derivative thereof, and is 2 to 20,
In accordance with another aspect of the present invention, there is provided a calcium metabolism-regulating agent comprising the above-mentioned peptide or a pharmacologically acceptable salt thereof as an effective ingredient.


DESCRIPTION OF THE PREFERRED EMBODIMENTS

By the term "calcium metabolism-regulating agent" used in the instant specification and appended claims is meant an agent effective for the remedy of a disease, one considered to be caused by an abnormal metabolism of calcium in the body, such as hypercalcemia or Paget's Disease of bone and osteoporosis
In the instant specification and appended claims, amino acids are abbreviated according to the method adopted by the Commission on Biochemical Nomenclature (CBN) of the International Union of Pure and Applied Chemistry and the International Union of Biochemistry (IUPAC-IUB). For example, the following abbreviations are adopted. L-histidine, Ile:
The peptide of the present invention can be synthesized according to the known liquid phase method or solid phase method customarily adopted for the synthesis of peptides. For example, if the solid phase method is adopted, the synthesis is carried out in the following manner.
More specifically, protected L-amino acids corresponding to the amino acids included in the above-mentioned formula are condensed in sequence from the C-terminal in an organic solvent-

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