Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1993-08-12
1997-11-18
Jagannathan, Vasu S.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 8, 514 12, 514 13, 514 14, 514 15, 514 16, 514 17, 530324, 530325, 530326, 530327, 530328, 530329, 530330, 530350, 530397, 530399, C07K 706, C07K 708, C07K 14635, A61K 3829
Patent
active
056887604
DESCRIPTION:
BRIEF SUMMARY
This invention relates to compounds and compositions which inhibit bone resorption, and to methods for inhibiting bone resorption. In particular, this invention is concerned with carboxyl terminal fragments of the polypeptide PTHrP (Parathyroid Hormone Related Protein) and derivatives thereof which inhibit bone resorption.
PTHrP (also known by the name Adenylate Cyclase Stimulating Factor--ACSF) is a protein which was first isolated and purified to homogeneity by Prof. T. J. Martin and colleagues from a squamous carcinoma (BEN cells) cell extract (Moseley et al., Proc. Natl. Acad. Sci. 85: 5048-5052, 1987). Nucleic acid encoding PTHrP was isolated and characterised by Suva et al. (Science 237: 893-896, 1987). The PTHrP gene encodes a polypeptide with a 31 residue signal sequence followed by a 5 residue basic Pro sequence and then the sequence of PTHrP. The human gene transcript can undergo alternative splicing to generate mature PTHrP comprising amino acids 1-139, 1-141 or 1-173. It is believed that the 1-141 form may predominate. The amino acid sequence of prepro PTHrP (SEQ ID NO:1) is depicted in FIG. 1, which shows the various splice variants (designated with an *).
PTHrP contains three principle domains. The N-terminal domain, extending from about residue 1 to residue 83 and termed the N-terminal domain, contains sequence which is related to PTH and contains the PTH receptor binding functionality of PTHrP. Thereafter in the C-terminal direction lies a highly basic region extending about from residues 84 to 106, termed the basic peptide, and finally the C-terminal peptide at about residues 107 to 141 or (107-139 or 107-173 in other splice variants).
The actions of PTHrP resemble closely those of PTH (parathyroid hormone) including activation of adenylate cyclase, simulation of bone resorption in organ culture by isolated osteoclasts in-vitro, and, promotion of phosphate excretion and kidney formation of cyclic AMP in-vivo. The PTHrP polypeptide is associated with non-metastic bone destruction and hypercalcemia, which result from excessive bone resorption.
Excessive bone resorption is associated with a number of non-malignant and malignant diseases, such as osteoporosis, Paget's disease of bone, humoral hypercalcemia of malignancy and metestic bone disease. In addition, astronauts experience increased bone resorption under conditions of zero gravity. Excessive bone resorption leads to brittle and weak bones which become increasingly susceptible to fracture and breakage, and deformation under body weight which may give rise to bone curvature and associated posture problems.
Hypercalcemia may also be associated with the calcification of organs and tissues, that is, the deposition of calcium within tissues and organs. Calcification may lead to impairment of organ function, and cell death. The kidneys are parcicularly susceptible to calcification, leading to reduced function and ultimately kidney failure with attendant serious complications.
It has now been discovered that carboxyl terminal fragments of PTHrP comprising at least amino acids 107-111 (that is, amino acids 107-111 through 107-173) and derivatives thereof are potent inhibitors of bone resorption. This surprising observation is in distinct contrast to the primary activity of "whole" PTHrP and N-terminal fragments thereof which promote bone resorption. This invention is predicated on this surprising discovery.
In accordance with a first aspect of this invention, there is provided a compound having bone resorption inhibitory activity which comprises a carboxyl terminal fragment of PTHrP consisting of at least amino acids 107-111 of PTHrP, or a derivative thereof, with the proviso that PTHrP 107-138 is specifically excluded.
The compounds in accordance with this aspect of the invention thus include any carboxyl terminal fragment of PTHrP from amino acids 107-111, through to amino acid 107-173, that is peptides comprising between 5 and 66 amino acids, and derivatives thereof. Such compounds include, for example, PTHrP(107-111), PTHrP(107-112), PTHrP(
REFERENCES:
patent: 4698328 (1987-10-01), Neer et al.
patent: 5312810 (1994-05-01), Wood et al.
Peninsula Laboratories, Inc. --Product availability notice, 1987.
Suva, et al. Science 237, 893 (1987).
Moseley, et al. PNAS 85, 5048 (1987).
Sone et al. 1992. Endocrinology 131:2742-6.
Whitfield et al. 1994. J. Cell. Physiol. 158:518-22.
Gagnon et al. 1993. J. Bone Min. Res. 8: 497-503.
Fenton et al. 1991. Endocrinology 129: 1762-8.
Fenton et al. 1991. Endocrinology 129:3424-6.
Kalu. 1991. Bone and Mineral 15: 175-92.
Bowie et al. 1987. Science 247: 1306-1310.
Barlet et al., "Synthetic parathyroid hormone-related peptide(1-34) fragment stimulates placental calcium transfer in ewes," J. Endocrin., 127:33-37 (1990).
Martin, T.J., "Hormones in the Coupling of Bone Resorption and Formation," Osteoporosis Int., 1:121-125 (1993).
Suda, T. et al., "Modulation of Osteoclast Differentiation," Endocrine Reviews, 13(1) 66-80 (1992).
Martin, T.J., et al., in "Handbook for Experimental Pharmacology," vol. 17, Physiology and Pharmacology of Bone, Mundy, G. and Martin, T.J. (eds.), Springer-Verlaag, Berlin, pp. 149-183 (1993).
Derwent Abstract Accession No. 90-294318/39, class B04, JP,A, 02-207099 (Tonen Corp.), 16 Aug. 1990.
Fenton Anna J.
Hammonds R. Glenn
Kemp Bruce E.
Martin Thomas J.
Nicholson Geoffrey C.
Dreger Walter H.
Genentech Inc.
Jagannathan Vasu S.
Kemmerer Elizabeth C.
The University of Melbourne
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