Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-06-11
2000-05-02
Woodward, Michael P.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530330, A61K 3800
Patent
active
060572957
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to oligopeptides derived from fragments of the C-reactive protein (hereinafter CRP), and to their use as immuno-modulating agents, and in the therapy of cardiovascular and inflammatory diseases.
CRP is a protein generally having a very low blood concentration, which rises up to two thousand times following inflammatory processes [J. J. Morley and I. Kushner, Am. New York Acad. Sci., 389, 406-418 (1989)]. F. A. Robey et al., J. Biol. Chem., 262, No. 15, 7053-7057 (1987) disclose three CRP tetrapeptide sequences very similar to the ones of tuftsin. The chemically synthetized tetrapeptides stimulate the phagocytic leukocytes and the production of superoxide, and induce mononuclear cells to produce interleukin 1, in a tuftsin-like manner. Like tuftsin, the three CRP tetrapeptides are rapidly metabolized and inactivated by proteases in vivo.
It has been now surprisingly found that chemically modified analogues of said CRP tetrapeptide fragments are endowed with immuno-modulating activity and are useful in the therapy of cardiovascular and inflammatory diseases, for example in the therapy of the septic shock.
Therefore, the present invention relates to oligopeptides of formula (I) threonine, leucine, isoleucine, valine, sarcosine, alanine, glycine and (C.sub.2-6)acyl-glycine, or is absent; leucine, isoleucine, valine, lysine, ornithine, N.alpha.-substituted by at least one (C.sub.1-6)alkyl, benzyl or (C.sub.2-6)acyl group; proline, leucine, isoleucine and valine; arginine, leucine and glutamine, optionally amidated at the C-terminal position, or is an agmatine residue, or is absent; absent; said compounds being further characterized in that the side-chain groups of the above aminoacid residues and of the agmatine residue may be optionally substituted by one or more groups selected from the group consisting of (C.sub.1-6)-alkyl, benzyl or (C.sub.2-6)acyl; and each of said aminoacid residues may be in D- or L-form at the C.alpha., or in form of one of the possible diastereoisomers or enantiomers;
A preferred group of compounds according to the invention are the ones of formula (I) wherein A.sub.1 is an aminoacid residue selected from the group consisting of glycine, threonine, leucine, isoleucine, valine, sarcosine, alanine (C.sub.2-6)acyl-glycine, or is absent; A.sub.2 is an aminoacid residue selected from the group consisting of lysine N.alpha.-substituted by a (C.sub.1-6)alkyl, benzyl or (C.sub.2-6)acyl group; A.sub.3 is proline; A.sub.4 is glutamine, leucine, arginine, optionally amidated at the C-terminal position, or an agmatine residue, or is absent; said aminoacid residue and of the agmatine residue may be optionally substituted by one or more substituents selected from the group consisting of (C.sub.1-6)alkyl, benzyl or (C.sub.2-6)acyl; and each of said aminoacid residue may be in D or L form on the C.alpha., or in form of one of the possible diastereoisomers or enantiomers;
As (C.sub.1-6)alkyl it is intended a group such as methyl, ethyl, propyl, i-propyl, butyl, sec-butyl, tert.-butyl, n-pentyl, 3-methyl-pentyl, n-hexyl group, and the relevant positional isomers. As (C.sub.2-6)acyl it is intended a group such as formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl and the relevant positional isomers.
Another object of the present invention relates to the use of the oligopeptides of formula (I) as immuno-modulating agents, and in the therapy of cardiovascular and inflammatory diseases, as the septic shock.
The compounds of the general formula (I) may be prepared employing peptide synthesis procedures, both in solid phase or in solution, known to the skilled in the art [see, for example, Merrifield, R. B., Biochemistry, 3, 1385 (1964)]. Unless otherwise mentioned, the aminoacid residues are intended to be used in L-configuration at the C.alpha..
Preferably, the synthesis is carried out in solution starting from the selected aminoacid and assembling the oligopeptide by a step-by-step addition of the desired aminoacids. Anyway, pre-constituted di- or tripeptide units may als
REFERENCES:
patent: 4353823 (1982-10-01), Chipens et al.
patent: 5521159 (1996-05-01), Verdini et al.
patent: 5578575 (1996-11-01), Verdini et al.
Hcaplus DN 112: 111693, Thiele et al., Proc. Natl. Acad. Sci. USA, 87 (1), 83-7, 1990.
Hcaplus DN 106: 61216, Hahn, WO 8604334, 1986.
Degrado, Advances In Protein Chemistry, vol. 39 pp. 51-118, 1988.
Buchta et al., Peptides (Fayetteville), 7(6), pp. 961-968, 1986.
Hocart et al., Innovation Perspect. Solid Phase Syn. Collect. Pap., Int. Symp., 1.sup.st Meeting, 413-20, 1990.
Murphy et al., Pept. Res., 1 (1), pp. 36-41, 1988.
Robey et al., Journal of Biological Chemistry, vol. 262, No. 15, pp. 7053-7057, 1987.
Fiedel, Immunology, 64, pp. 487-493, 1988.
Wieczorek et al., Peptides, vol. 15, No. 2, pp. 215-221, 1994.
Cappelletti Silvana
Caretto Patrizia
Gromo Gianni
Leoni Flavio
Marcucci Fabrizio
Delacroix-Muirheid C.
Italfarmaco S.p.A.
Schneider Walter H.
Woodward Michael P.
LandOfFree
Oligopeptides derived from C-reactive protein fragments does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Oligopeptides derived from C-reactive protein fragments, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Oligopeptides derived from C-reactive protein fragments will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-1593866