Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-06-05
2004-11-23
Weber, Jon P. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C530S328000
Reexamination Certificate
active
06821954
ABSTRACT:
TECHNICAL FIELD
This invention relates to novel compounds derived from amylin. The invention also relates to pharmaceutical compositions containing such compounds and their use in the treatment of bone disorders where stimulation of bone growth is required.
BACKGROUND OF THE INVENTION
Amylin is a 37-amino acid peptide co-secreted with insulin from the beta cells of the pancreatic islets. It is structurally related to calcitonin gene-related peptide (CGRP) and more distantly to calcitonin itself. As a result of these similarities and the fact that calcitonin has potent effects on osteoclasts, the actions of amylin in bone have been studied. Amylin mimics some of the effects of calcitonin on bone resorption. It stimulates cyclic AMP formation and induces quiescence in osteoclasts, reducing the amount of bone resorbed. Similar effects are demonstrable in bone culture.
Amylin 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.
Lys-Cys-Asn-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 30
Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO:1)
31 35
The native molecule contains a disulphide bridge between the cysteine residues shown at positions 2 and 7 in the primary structure. Further, it is amidated at the 3′-end and it 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.
The use of amylin and amylin agonists for the stimulation of bone growth is described and claimed in our related patent application PCT NZ 95/00062 (published as WO 96/62269).
Amylin has been found to affect osteoblasts. There is a dose-dependent stimulation of osteoblast proliferation by amylin in concentrations as low as 10
−11
M. Histomorphometric indices of bone formation are increased in vivo following local injection of the peptide. The anti-osteoclastic potency of amylin is substantially reduced in the absence of the carboxyl terminal amide group.
However, details of the structure-activity relationships for the bone effects of amylin are unclear. The actions of amylin to stimulate bone formation and inhibit bone resorption make it an attractive candidate for the therapy of osteoporosis and for the promotion of the repair of local bone defects. The full peptide would be expensive to manufacture, not be active orally, and might have deleterious effects on carbohydrate metabolism.
Amylin has been implicated in the pathogenesis of type 2 diabetes, in part, as a result of amyloid deposition in the pancreatic islets. However, the action of amylin on carbohydrate metabolism requires the intact peptide. Its propensity to form amyloid is dependent, in part, on the amino acids between positions 25 and 29. Thus a peptide that exhibits osteoblast proliferative effects and which has no effect on carbohydrate metabolism or a tendency to lead to amyloid formation is highly desirable as a stimulant of bone formation in the management of osteoporosis and other bone disorders.
DISCLOSURE OF THE INVENTION
While intact amylin produces the greatest maximal effect on osteoblast proliferation, we have now surprisingly found that N-terminal amylin-(1-8), also stimulates osteoblast proliferation, without the effects on carbohydrate metabolism or a tendency to lead to amyloid formation possessed by the whole peptide.
The invention provides compounds which are useful for stimulating bone growth in an animal and is useful for preventing bone deterioration in an animal.
The invention also provides a pharmaceutical composition containing such compounds together with a pharmaceutically acceptable carrier preferably in orally administrable form.
The compounds of this invention are those of formula I.
R
1
-Cys-Asn-Thr-Ala-Thr-Cys-R
2 (SEQ ID NO:
2) (I)
where R
1
is absent, Lys or a functionally effective group and R
2
is absent, or Ala or a functionally effective group; or a functionally effective derivative thereof.
The invention also provides a method of stimulating bone growth comprising subjecting bone to the effect of an effective amount of a compound of formula I.
The method of the invention will be particularly useful for treatment of osteoporosis of any cause, bone loss or malignancy, or endocrine disorders 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 further 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 the amylin fragment.
By this aspect of the invention it is envisaged that patients at risk of bone deterioration will be given a regular dose of the amylin fragment to prevent likely bone deterioration. Patients at most risk are post menopausal women, usually at age above 50, and men over 60 years of age.
Administration within the scope of the invention can also be after bone density has deteriorated beyond the normal level. Normal bone density means bone density within two standard deviations of the mean value for race, age and sex. In view of the effect of inhibiting osteoclast activity and the effect of stimulating bone growth, treatment with the amylin fragment is capable of reversing bone loss.
The compounds of this invention are the 2 to 7 amino acids of amylin with a disulphide bond between the 2 and 7 cysteine groups. Amylin (1-8) is active while amylin (1-8) with 2 to 7 disulphide bond removed is inactive and blocks the activity of amylin (1-8). The 2 to 7 disulphide bond is therefore necessary for osteoblast proliferation.
The N-terminal group R
1
can be absent but is preferably lyseine. Functionally effective groups as R
1
include derivatives of the N-terminus eg acid addition salts and one or more alternative amino acids and derivatives thereof in which the compound has osteoblast stimulating activity. Similarly the C-terminal group R
2
can be absent but is preferably alanine and is preferably amidated. Functionally effective groups as R
2
include derivatives such as amides and one or more alternative amino acids and derivative thereof where the compound has osteoblast stimulating activity without an effect on carbohydrate metabolism or a tendency to lead to amyloid formation.
Functionally effective derivatives of the compounds of formula I include agonists and related peptides in which one or more of the 2 to 7 amino acids are replaced by other amino acids and which stimulate osteoblast activity without an effect on carbohydrate metabolism or a tendency to lead to amyloid formation.
The compounds of the invention can be produced by known methods but are preferably synthesised using standard solid phase peptide synthesis techniques. For example, the compounds can be prepared on methylben
Cooper Garth James Smith
Cornish Jillian
Coy David H
Reid Ian Reginald
Auckland UniServices Limited
Fish & Richardson P.C.
Weber Jon P.
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