Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-06-01
1997-12-16
Tsang, Cecilia J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
530313, 530328, A61K 3809, C07K 723
Patent
active
056985223
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to peptides having pharmacological activity, to pharmaceutical compositions containing such peptides, and to a medical method of treatment.
More particularly, the present invention coheres certain decapeptides, modified in the 6-position which are antagonists of luteinizing-hormone-releasing-hormone (LHRH), to pharmaceutical compositions containing these peptides, and to a method of inhibiting LHRH activity in a mammal in need of such treatment.
BACKGROUND OF THE INVENTION
The gonadotropins, follicle stimulating hormone (FSH), luteinizing hormone (LH), and chorionic gonadotropin (CG) are required for ovulation, spermatogenesis, and the biosynthesis of sex steroids. A single hypothalamic hormone, gonadotmpin-releasing-hormone (GnRH, also known as luteinizing-hormone-releasing-hormone, LHRH) is responsible for regulating the secretion of both FSH and LH in mammals.
LHRH has the structure -Leu.sup.7 -Arg.sup.8 -Pro.sup.9 -Gly.sup.10 -NH.sub.2 the decapeptide chain.
LHRH is released from the hypothalamus and binds to a receptor on the pituitary gland, causing the release of LH and FSH which subsequently act on the gonads to stimulate the synthesis of steroid sex hormones. The pulsatile release of LHRH, and thereby the release of LH and FSH, controls the reproductive cycle in animals and man. Acute doses of LHRH agonists increase the levels of LH and steroidal sex hormones in both animals and humans. Paradoxically, chronic doses of LHRH agonists suppress the levels of LH and steroidal sex hormones. Consequently, the effect of multiple doses of LHRH agonists is to suppress estrogen formation in females and testosterone production in males. The same effect is observed in both animals and humans after administration of either acute or chronic doses of LHRH antagonism.
In recent years considerable research effort has been expended on finding synthetic analogs of LHRH. These efforts have produced a number of LHRH agonists and antagonists, with considerable research being devoted to finding peptides which mimic the anti-ovulatory potency of LHRH while minimizing undersirable side-effects such as stimulation of histidine release.
SUMMARY OF THE INVENTION
The present invention provides a class of decapeptide compounds which are potent antagonists of LHRH activity and which are characterized by having an .OMEGA.-amino-functionalized side chain on the D-aminoacyl residue at position 6. The .OMEGA.-amino group of this side chain is further derivatized by the attachment of an extending group which likewise has a terminal amino group which is capped by an acyl group. In particular, the present invention provides a peptide or pharmaceutically aceaeptable salt thereof of the formula -R.sup.9 -T.sup.10 N-acetyl-D-3-(naphth-2-yl)alanyl; N-acetyl-D-phenylalanyl; N-acetyl-D-3-(4-hlorophenyl)alanyl; N-acetyl-D-3-(quinolin-3-yl)alanyl; N-acetyl-azaglycyl, and N-acetylsacrosyl.
The second aminoacyl residue in the decapeptide chain, D, is selected from the group consisting of D-phenylalanyl; D-3-(4-chlorophenyl)alanyl; D-3-(4-fluorophenyl)alanyl; and D-3-(naphth-2-yl)alanyl.
The residue E is selected from the group consisting of D-3-(pyrid-3-yl)alanyl; D-3-(naphth-1-yl)alanyl; N-acetyl-D-3-(quinolin-3-yl)alanyl, D-3-(thiazol-2-yl)alanyl; and
G is an aminoacyl residue selected from the group consisting of L-seryl; L-seryl(O-benzyl); and N(R.sup.1)-L-seryl where R.sup.1 is hydrogen or alkyl of from one to four carbon atoms.
The fifth aminoacyl residue in the decapeptide chain, J, is selected from the group consisting of N(R.sup.1)-L-tyrosyl(O-methyl); N(R.sup.1)-L-Phenylalanyl; N(R.sup.1)-L-cyclohexylalanyl; N(R.sup.1)-L-arginyl; and N(R.sup.1)-L-homoarginyl; where R.sup.1 is as defined above.
L is a D-aminoacyl residue having the structure ##STR1## where X is selected from the group consisting of --(CH.sub.2).sub.n -- where n is an integer of from one to six, inclusive, and ##STR2##
Y is an aminoacyl residue selected from the group consisting of D-alanyl; L-alanyl; 4-aminobutyryl; 5
REFERENCES:
patent: 5110904 (1992-05-01), Haviv et al.
Dayhoff, M. `Atlas of Protein Sequence and Structure 1972`, Wash. D.C.:National Biomedical Research Foundation, vol. 5, p. 76, 1972.
Schulz et al. `Principles of Proetin Structure`, New York: Springer-Verlag, pp. 14-16, 1979.
Ljungquist, Anders et al. Z. Naturforsch., B: Chem. Sci. 46(9), 1231-6 Article Title Design, Synthesis & Biological Evaluation of Antagonists of LHRH Criteria of Potency, Safety & Solubility, 1991.
Fitzpatrick Timothy D.
Greer Jonathan
Haviv Fortuna
Mort Nicholas A.
Nichols Charles J.
Abbott Laboratories
Anand Mona
Gupta Anish
Tsang Cecilia J.
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