Therapeutic method and compounds of use therein

Details Therapeutic method and compounds of use therein Therapeutic method and compounds of use therein

1997-01-08

1999-07-13

Carlson, Karen Cochran

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

530324, 530300, A61K 3700, A61K 3702, C07K 14435

Patent

active

059226773

DESCRIPTION:

BRIEF SUMMARY
TECHNICAL FIELD

This invention relates to the use of amylin as an agent for stimulation of bone growth and hence its use in the treatment of bone disorders where stimulation of bone growth is required and novel compounds for use therein.


BACKGROUND OF INVENTION

Amylin is a 37-amino acid peptide cosecreted with insulin from the beta cells of the pancreatic islets. It was first reported by Cooper et al in Proceedings of the National Academy of Sciences USA 84, 8628 (1987) and is the subject of European Patent 289287. Amylin has the following peptide sequence:


Lys-Cys-Ans-Thr-Ala-Thr-Cys-Ala-Thr-Gln- 1 5 10 Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser- 11 15 20 Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr- 21 25 20 Asn-Val-Gly-Ser-Asn-Thr-Tyr 31 35 residues shown at positions 2 and 7 in the primary structure, is amidated at the 3'-end, and is formed as a propeptide.
European Patent 289287 reports a number of novel biological effects including enhancement of hepatic glucose output, increased production of lactate from skeletal muscle and reduced action of insulin in skeletal muscle.
Amylin is also reported in European Patent 408284 as having value for treatment of bone disorders and calcium imbalance. The patent specification attributes the activity of amylin to an inhibition of osteoclast motility.


DISCLOSURE OF THE INVENTION

We have now found that administration of amylin stimulates bone growth. We believe this is the first report of the use of amylin causing measurable bone formation through increased proliferation of osteoblasts.
By the terms amylin or amylin agonist as used herein we mean amylin or any functionally effective derivative or fragment thereof or related peptide which binds to the amylin receptor and lead to amylin like effects. Fragments are described for example in EP 289287 which is herein incorporated by reference.
The invention therefore provides a method of stimulating bone growth comprising subjecting bone to the effect of an effective amount of amylin or an amylin agonist.
The invention further provides a method of stimulating bone growth through increasing osteoblast proliferation comprising subjecting the bone to the effect of an effective amount of amylin or an amylin agonist.
The method of the invention will be particularly useful for treatment of osteoporosis, bone loss of malignancy, or endocrine disorders or arthritides or immobility and disuse and in fractures by enabling the patient to reverse previous bone loss. The method can be used for treatment of bone disorders in all animals, e.g. mammals particularly humans, cattle, horses, dogs and cats.
The invention also provides a method of prophylactically increasing or maintaining bone density in a subject having a substantially normal bone density comprising the step of administering an effective amount of amylin or an amylin agonist.
By this aspect of the invention it is envisaged that patients at risk of bone deterioration will be given a regular dose of amylin or an amylin agonist to prevent likely bone deterioration. Patients at most risk are post menopausal women usually at age above 50 and men beyond 60. By "normal bone density" is meant within two standard deviations of the mean value for race, age and sex.
Administration within the scope of the invention can also be after bone density has deteriorated beyond the normal level. In view of the previously noted effect of inhibiting osteoclast activity and the effect noted by us of stimulating bone growth, treatment with amylin or an amylin agonist is capable of reversing bone loss.
Treatment of mammals can be with the homologous or heterologous amylin. Suitable amylin or amylin agonists can be those derived from animals, e.g. humans and other mammals e.g. rat, monkey, dog, cat, mouse, guinea pig, hamster, degus, rabbit, hare. The structure of these various peptides is reported in Endocrine Reviews 1994, 15 (2) 163 by Garth J S Cooper which is herein incorporated by reference.
Amylin and amylin agonists can be produced by methods well known in the art, e.g. as set for

REFERENCES:
patent: 5124314 (1992-06-01), Cooper
patent: 5298605 (1994-03-01), Westermark et al.
patent: 5405831 (1995-04-01), MacIntyre
Ried et al. Parathyroid hormone depresses cytosolic pH and DNA synthesis in osteoblast-like cells .COPYRGT. 1988, Am. J. Physiol. 255:E9-E15.
Calcif. Tissue Int. vol. 56, pp. 54-61 (1995). D. F. Romero et al., "Amylin Increases Bone Volume but Cannot Amelionate Diabetic Ostoperia". See in particular Abstract and p. 57.
Biochem. Biophys. Res. Comm., vol. 207, No. 1, pp. 133-139, Cornish, J. et al., "Amylin Stimulates Osteoblast Proliferation and Increases Mineralized Bone Volume in Adult Mice", Feb. 6, 1995. See in particular Abstract, pp. 134, 136 and 137.
WO 88/02863 A (University of Minnesota), Apr. 21, 1988. See "Experimental Portion A", pp. 9 and 10.
Endocrine Reviews, vol. 15, No. 2, pp. 163-201 (1994) Cooper, G.J.S. "Amylin Compared with Calcitonin Gene-Related Peptide: Structure, Biology, and Relevance to Metabolic Disease". See p. 186.
Bone, vol. 14, pp. 167-172 (1993), Pietschmann, P. et al., Inhibitory Effect of Amylin on Basal and Parathyroid Hormone-Stimulated Bone Resorption in Cultured Neonatal MouseCalvaria.
Trends in Endocrinology and Metabolism, vol. 4, No. 8, pp. 255-259 (1993). Mone Zaidi et al. "Amylin in Bone Conservation: Current Evidence and Hypothetical Considerations".
J. Cellular Physiology vol. 153, pp. 6-14 (1992) Tamura, T., et al "Mechanism of Action of Amylin in Bone". See Abstract, pp. 7,9 to 13 in particular.
Biochem. Biophys. Res. Comm. vol. 162, No. 2, pp. 876-881 (1989). Datta, H.K. et al "In vivo and In Vitro effects of amylin and amylin-amide on calcium metabolism in the rat and rabbit".
Proc. Nat. Acad. Sci. USA, vol. 184, pp. 8628-8632 (1978) Cooper, G.J.S. et al "Purification and characterisation of a peptide from amyloid-rich pancreases of Type 2 diabetic patients".
Experimental Physiology, vol. 78, pp. 183-196 (1993). A.S.M. Towdihul Alam et al "Amylin Inhibits Bone Resorption by a Direct Effect on the Motility of Rat Osteoclasts". See in particular p. 195.
J. Bone Miner. Research vol. 15, S229, Abstract 621 (1990) Datta, H.K. et al Amylin-amide competes with CGRP bindin sites on osteoblast-like osteosarcoma cells.
J. Bone Miner. Research vol. 7, No. 9, pp. 1113-1116 (1992) Wimala Wansa, S.J. et al "Hypocalcemic Actions of Amylin Amide in Humans". See in particular p. 1114.
Datta et al 1990 Biochem. Soc. Trans. 18:1276.
Tamura et al 1992 Calif. Tissue Int. 50(Suppl 1):A42.

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