Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-02-17
1997-09-23
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 15, 530324, 530328, A61K 3804, A61K 3816
Patent
active
056704828
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/01297, filed Jun. 18, 1993.
FIELD OF THE INVENTION
The present invention relates to peptides which show improved Neuropeptide Y antagonism, to pharmaceutical compositions containing such peptides and to their use in animal and human medicine.
Neuropeptide Y (NPY) is a 36 residue amidated peptide first isolated from brain tissue in 1982 (Tatemoto K., Carlquist M. and Mutt V., Nature 296; 659-660, 1982). The peptide is widely distributed throughout the mammalian central nervous system and the peripheral sympathetic nervous system; in the latter it is colocalised with norepinephrine. Peripheral administration of NPY induces vasoconstriction in many vascular beds and also potentiates the vasoconstriction induced by norepinephrine, and other vasoactive substances, in vessels where NPY does not have a direct effect. NPY functions in the brain as an appetite stimulant and promotes release of prolactin growth hormone and leutinizing hormone. NPY is known to elicit its effect by binding to receptors located in the central and peripheral nervous system. EPO 355 794 and DE 38 11 193 describe derivatives of NPY which may bind to such NPY receptors and act as antagonists of NPY activity.
SUMMARY OF THE INVENTION
A class of peptides has now been found which are effective NPY antagonists. These antagonists suppress the action of endogenous NPY and are therefore useful in cardiovascular disorders, hypertension and hypertensive crisis, vasospasm, cerebral or coronary vasospasm (eg. stroke), eating disorders, depression and also in glaucoma. Such compounds are particularly suitable for use in combination with angiotensin converting enzyme (ACE) inhibitors and calcium antagonists.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a peptide of formula (I), or a multimer thereof or a salt thereof: (I) ##STR1## in which n=0-4.
A multimer according to the present invention includes a dimer. Such normally occur when peptides containing Gly residues are bridged at the alpha position by a group selected from the following; ##STR2## in which n is as defined herein. Alternatively, such multimers may also occur when peptides are lactam bridged. Such multimers can contain one or more such bridges, preferably two.
It is preferred that a peptide of the invention is used in the form of a dimer.
A salt of a peptide or a multimer of the invention is also included within the scope of the present invention. Such a salt is prepared according to any of the methods well known in the art.
A pharmaceutically acceptable salt of a peptide or a multimer of the invention is also included within the scope of the present invention. Suitable pharmaceutically acceptable salts include acid addition salts when the peptide is sufficiently basic i.e., contains one or more basic residues.
A suitable pharmaceutically acceptable acid addition salt of a peptide of the invention may be formed with an inorganic acid, for example hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or with an organic acid, for example acetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid or trifluoroacetic acid.
Preferred examples of X.sub.2 include Cys and Glu.
Preferred examples of X.sub.3 include Pro.
Preferred examples of X.sub.4 include Cys Dpr and Orn.
Preferred examples of X.sub.5 include Tyr.
Preferred examples of X.sub.6 include Leu.
Preferred examples of R.sub.2 include --(CH.sub.2).sub.n NH.sub.2 in particular wherein n is 0.
A preferred sub-class of a peptide of formula (I), or a multimer thereof, or a salt thereof, is that wherein X.sub.5 is Tyr, X.sub.6 is Leu, and R.sub.1 and R.sub.2 have the meaning described above.
The following abbreviations for amino acid residues are used throughout:
Aib for 2-methyl alanine, Arg for arginine, Asn for asparagine, Asp for aspartic acid, Cys for cysteine, Dpr for diaminoproprionic acid, Glu for glutamic acid, Gly for glycine, Ile for isoleucine, Leu for leucine, Orn for ornithine, Phe for phenylalanine, Pro for proline,
REFERENCES:
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patent: 5328899 (1994-07-01), Boublik et al.
patent: 5330979 (1994-07-01), Siren et al.
Beck-Sickinger et al., "Structure-activity Relationships of Neuropeptide Y," Peptides, Proceedings of the Twelfth American Peptide Symposium, 17-19 (Jun. 16-21, 1991).
Forest et al., "Structural Study of the N-Terminal Segment of Neuropeptide Tyrosine," J. Med. Chem., 33(6), 1615-1619 (1990).
Daniels Alejandro Jose
Heyer Dennis
Landavazo Antonio
Leban Johann Jakob
Spaltenstein Andreas
DeWitt LaVonda E.
Glaxo Wellcome Inc.
Gupta Anish
Hrubiec Robert T.
Tsang Cecilia J.
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