Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1985-02-27
1987-05-05
Phillips, Delbert R.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514808, 530307, A61K 3724, C07K 736
Patent
active
046633090
DESCRIPTION:
BRIEF SUMMARY
The invention described herein was made in the course of work under a grant from the National Institutes of Health.
This invention relates to novel peptide hormones which exhibit calcitonin-like activity, to the pharmaceutically acceptable non-toxic salts thereof, to compositions containing said hormones, and to methods of lowering serum calcium levels by the administration of said hormones.
Calcitonin is a peptide hormone with a molecular weight of approximately 3,500 daltons which is produced by the parafollicular cells; these cells are scattered throughout the thyroid in mammals but in lower animals constitute a distinct organ, the ultimobranchial body. The hormone regulates serum calcium concentrations by opposing the bone and renal effects of parathyroid hormone and inhibiting bone resorption of calcium, resulting in hypocalcemia, hypophosphatemia, and decreased urinary calcium concentrations. Calcitonin is therefore used in the treatment of Paget's Disease, hyperparathyroidism, idiopathic hypercalcemia of infancy, osteolytic bone metatases, and to counteract the osteolytic effect of overdoses of vitamins A and D.
Calcitonins from at least seven different species, and the two isohormones of salmon calcitonin, have been sequenced and characterized biologically and a number of synthetic analogs have been studied, but few clear correlations between structure and function have been made. The common form of the hormone consists of 32 amino acids with a disulfide bridge between cysteine residues at positions 1 and 7 and prolinamide at the carboxy terminus. All natural forms of calcitonin have a hydrophilic amino acid at position 15, usually aspartate or glutamate. The mammalian forms all have aromatic amino acids at positions 12, 16, and/or 19, while the ultimobranchial peptides do not. As a group, mammalian calcitonins are between 10 and 50 times less potent than those of ultimobranchial origin (Guttman, S. in Calcitonin 1980: Chemistry, Physilogy, Pharmacology and Clinical Aspects (Pecile, A., ed.) (Exerpta Medica, Princeton, N.J., 1981), p. 11). Otherwise the structures of the various calcitonins differ markedly from each other; human calcitonin differs from porcine calcitonin at 18 of the 32 residues. It is generally recognized that the cysteines at positions 1 and 7 taken together may be replaced by 2-aminooctanedioic acid, resulting in the analogous structure wherein the disulfide bridge of the cysteines has been replaced by an ethylene bridge. For a general review, see MacIntryre, I., I. M. A. Evans, H. H. G. Hobitz, G. F. Joplin, and J. C. Stevenson, Arth. Rheum. 23:1139-1147 (1980); Guttman, supra.
Because of its therapeutic value, calcitonin is in great demand. Of the known calcitonins and their analogs, only three, salmon, porcine, and human, are commercially available. Porcine calcitonin is isolated and purified at great expense from pork glands, whereas salmon and human calcitonin are primarily synthesized in vitro. Salmon calcitonin is the most active of the known calcitonins, and porcine is the most active commercially available mammalian calcitonin. However, because foreign calcitonins tend to trigger an antigenic response, and because human calcitonin is only weakly active, there is a need for improved synthetic alternate peptide hormones with calcitonin-like activity.
Maier, R., B. Kamber, B. Riniker, and W. Rittel, Clin. Endocrin. 5(Suppl.):327s-332s (1976) showed that sequentially substituting leucine for aromatic amino acids in positions 12, 16, and 19 of human calcitonin significantly increased its efficiency. However, they were unable to obtain an analog with activity equal in potency to salmon calcitonin. There is therefore a need to further understand the elements required for activity so that these compounds can be modified to introduce desired pharmaceutical characteristics, such as increased half-life or oral activity, without losing efficacy.
It has now been discovered that compounds of the Formula I: ##STR3## wherein R.sub.1 is a moiety selected from the group consisting of ##S
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Kaiser Emil T.
Moe Gregory R.
Phillips Delbert R.
Shimei Barbara A.
University Patents Inc.
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