Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1993-07-23
1995-02-14
Hill, Jr., Robert J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530331, A61K 3702, C07K 508
Patent
active
053896157
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to peptides, to their preparation and to their use.
The term Interleukin-1 (IL-1) describes two pluripotent inflammatory proteins produced by activated macrophages and other cell types. Two genes encode the two forms of IL-1, IL-.alpha. and IL-1.beta., which have amino acid sequences with only 26% homology. Nevertheless, IL-1.alpha. and IL-1.beta. are reported to have similar biological activities with few exceptions. Indeed both molecules appear to act at the same receptor. There is good evidence that both have a role as a haemopoietic growth factor and in the pathology of a number of inflammatory diseases. Also, IL-1 has anti-tumor activity.
Since IL-1 releases prostaglandins, which sensitise pain receptors in man and in experimental animals, IL-1.alpha. and IL-1.beta. were tested for hyperalgesic activity. It was found that IL-1.beta. is an extremely potent hyperalgesic agent with about three thousand times the activity of IL-1.alpha.. Further, a family of peptides has been discovered which very effectively antagonise hyperalgesia induced by IL-1.beta. and by other inflammatory agents. These peptides may therefore be used as analgesics.
Accordingly, the present invention provides the use, in the preparation of a medicament for use in the prevention or treatment of pain, of a peptide of formula (I): ##STR1## wherein X is
H.sub.2 N--[CH.sub.2 ].sub.4 --CH(NH.sub.2)--C(.dbd.0)-- or
H.sub.2 N--C(.dbd.NH)--NH--[CH.sub.2 ].sub.3 --CH(NH.sub.2)--C(.dbd.0)--,
and Y is a hydroxy group or an amino acid residue; excluding Lys-Pro-Arg, Arg-Pro-Tyr, Arg-Pro and Lys-Pro. The peptide of formula (I) may be in the form of its C-terminal amide. A pharmaceutically acceptable salt of the peptide of formula (I) or its C-terminal amide may be used.
An article by D. B. Richards and J. M. Lipton in Peptides 5 (1984) 815-817 discloses the antipyretic effect of the tripeptide Lys-Pro-Val in febrile rabbits. Some other peptides of formula (I) are known but some are novel. Accordingly, the present invention provides a peptide of formula (I), C-terminal amide or pharmaceutically acceptable salt as defined above, with the further proviso that the peptide of formula (I) is not:
(i) a peptide of formula (III):
(ii) a peptide of formula (IV):
(iii) Arg-D-Pro-Pro, Arg-D-Pro-Lys, D-Lys-Pro or Arg-D, L-Pro.
The invention also provides a process for the preparation of the novel peptides of formula (I), their C-terminal amides and the pharmaceutically acceptable salts of these peptides and amides, which process comprises chemically synthesising a said peptide, optionally as a C-terminal amide, and, if desired, converting the resulting compound into a pharmaceutically acceptable salt thereof.
Each of the constituent amino acid residues of the peptide of formula (I) which is chiral may be present as either the D or the L optical isomer. The D isomer is particularly preferred in the case of the central proline residue. Using the three letter system of denoting amino acids, in which the symbols denote the L configuration of the chiral amino acid unless otherwise stated, X may be Lys, D-Lys, Arg or D-Arg. Indeed a peptide of formula (I) may be present as a racemic mixture or as an optically pure isomer. Preferably X is Lys or D-Lys.
When Y is a hydroxy group the peptide of formula (I) is a dipeptide. However, tripeprides are preferred. Y is typically an .alpha.-amino acid residue. More particularly Y is generally a naturally occurring amino acid residue.
Preferably Y is a neutral amino acid residue. An aliphatic amino acid residue is preferred to an aromatic amino acid residue and a neutral amino acid residue to an acidic amino acid residue. In particular Y may be a threonine or valine residue. When Y is a threonine residue, one embodiment of the peptide of formula (I) is a peptide of the following formula (II): ##STR2##
Y may also be a residue derived from glycine. Y may be an alanine or serine residue or, preferably, a leucine or isoleucine residue. Y may also suitably be an acidic amino acid residue. Y is then ty
REFERENCES:
patent: 3778426 (1973-11-01), Najjar
patent: 4127534 (1979-11-01), Coy et al.
patent: 4855407 (1989-08-01), Wang
patent: 5028592 (1991-07-01), Lipton et al.
"Nomenclature and Symbolism for Amino Acids and Peptides" Europ. Jour. of Biochemistry 138, pp. 9-37.
Ferreira et al "Central and Peripheral Antialgesic Action of Aspirin . . . " Europ. Jour. of Pharmacology, 58 (1978) pp. 39-48.
Smolders et al "Conformational Study by .sup.13 C nuclear Magnetic . . . " Canadian Jour. of Biochemistry, vol. 58, No. 11 Nov. 1980.
Moncada et al "Pain and Inflammatory Mediators" Handbook of Exp. Pharmacology, vol. 150/61 1978.
Gorne et al "Action of Substance P and Substance P fragments . . . " Pharmazie, 37, H.4 (1982).
Scientific American, vol. 253 Oct. 1985, p. 76.
Ferreira et al, Nature vol. 334, No. 6184 pp. 698-700 (Aug. 25, 1988).
Fujino et al, Chemical Abstracts 90, 104363v (1979)
Auriault et al, FEBS Letters 153 1, pp. 11-15 (Mar. 1983).
Nicolaides et al, Int. J. Peptide Protein Res. 25 (1985) pp. 435-441.
Furuta et al, J. Pharmacol. 83(1), pp. 43-48 (1984).
Herman et al, Naturwissenschaften 72(2) pp. 85-86 (1985).
Goerne et al, Pharmazie 37(4) 299-300 (1982).
Eberle, A. N. (ed) "The Melanotropins, chemistry . . . " Karger Press, 1988, pp. 336-337 and 346-348.
Hiltz, M. E. et al, "Anti-inflammatory activity of . . . " Pergamon Press, USA, vol. 12, pp. 767-771.
Lipton, J. M. & Catania, A. ".alpha.-MSH peptides modulate . . . " Pergamon Press, USA, 1992, pp. 123-136.
McLauglin, C. L. et al "Food intake and body temperature . . . " Physiology & Behavior, Pergamon Press, USA, vol. 52 (1992), pp. 1155-1160.
Chemical Abstracts #111:73430a, vol 111, 1989.
Richards et al. "Effect of .alpha.-MSH 11-13 (Lysine-Proline-Valine)", Peptides (1984) pp. 815-817, vol. 5.
Dryland et al. "Peptide Synthesis 8." Perkin Transation 1, 125, 1986.
Goerne et al, Pharmazie 37 (4) 299-300.
Bristow Adrian F.
Ferreira Sergio H.
Poole Stephen
British Technology Group Ltd.
Hill Jr. Robert J.
Marshall S. G.
LandOfFree
Peptides and pharmaceutical composition thereof in the treatment does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Peptides and pharmaceutical composition thereof in the treatment, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptides and pharmaceutical composition thereof in the treatment will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-288030