Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-02-23
2002-09-24
Borin, Michael (Department: 1631)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C930S130000
Reexamination Certificate
active
06455499
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to LHRH antagonist peptides and uses thereof.
Luteinizing hormone (LH) and follicle-stimulating hormone (FSH) are hormones released by the pituitary gland. These hormones regulate the functioning of the gonads and the production and maturation of gametes. LH and FSH are generally released by the pituitary gland upon prior release of triggering hormone from the hypothalamus. Luteinizing hormone-releasing hormone (LHRH; also known as gonadotropin-releasing hormone or GnRH) is one of the principal hypothalamic hormones which triggers the release of LH. Thus, release of LHRH represents a control point in the physiological regulation of gonadal function. The structure of mammalian LHRH has been determined, and has been found to be a decapeptide:
LH release is necessary for ovulation; thus, compounds which inhibit LH release by blocking the action of LHRH are useful as contraceptive agents. LHRH antagonists are also useful for regulating secretion of gonadotropins in male mammals, and thus can be used as male contraceptives. In addition, LHRH antagonists can be used in the treatment of sex-hormone dependent cancers (for example, prostate cancer), where increased levels of gonadotropins increase the rate of tumor growth.
Many modified LHRH analog peptides have been synthesized in an attempt to increase the potency of the antagonists, preferably while also increasing the resistance of the antagonist to enzymatic degradation. For example, synthetic LHRH antagonist peptides which incorporate modified or unnatural amino acids have been tested. Common substitutions include, for example, substitution of 4-Cl-D-Phe for His at position 2, or substitution of D-Ala-NH
2
for Gly-NH
2
at position 10.
One problem frequently encountered in LHRH antagonist peptides is the occurrence of histamine-releasing activity. This histamine-releasing activity represents a serious obstacle to the clinical use of such antagonists because histamine release results in adverse side effects such as edema and itching. Thus, LHRH antagonist peptides which have low histamine releasing activity are particularly desirable. Although the LHRH antagonist and histamine-releasing properties are not necessarily related, very few prior art compounds combine low histamine-releasing activity with high LHRH antagonist activity. Many prior art LHRH antagonist peptides also suffer from poor water-solubility, which complicates formulation of the antagonist for administration.
SUMMARY OF THE INVENTION
The present invention features LHRH antagonist peptides, methods of modulating LHRH activity, and methods of treating a subject with the antagonists of the invention. In one embodiment, an LHRH antagonist comprises a peptide compound, wherein a residue of the peptide compound corresponding to the amino acid at position 6 of natural mammalian LHRH comprises D-Lys(Imdac), D-Lys(Ppic), D-Lys(Dodac), D-Lys(pGlu), D-Lys(Otac) and D-Lys(Onic) or a moiety selected from the group consisting of a dipolar moiety, a sulfonium moiety, a receptor-modifying moiety and a small polar moiety, such that the peptide compound has LHRH antagonist activity, with the provisos that the dipolar moiety is not a zwitterionic pyridinium and the residue is not D-Cit, D-Hci or a lower alkyl derivative of D-Cit or D-Hci. Preferably, the peptide compound comprises about 8 to about 12 residues. More preferably, the peptide compound comprises 10 residues.
In another embodiment, the invention provides a peptide compound comprising a structure:
A-B-C-D-E-F-G-H-I-J
wherein
A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar, or Ac-D-Pal;
B is His or 4-Cl-D-Phe;
C is Trp, D-Pal, D-Nal, L-Nal, D-Pal(N—O), or D-Trp;
D is Ser;
E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;
F is D-Lys(Imdac), D-Lys(Ppic), D-Lys(Dodac), D-Lys(pGlu), D-Lys(Otac), D-Lys(Onic) or a structure:
wherein
R and X are, independently, H or alkyl; and
Y comprises a moiety selected from the group consisting a dipolar moiety, a sulfonium moiety, a receptor-modifying moiety and a small polar moiety, the provisos that the dipolar moiety is not a zwitterionic pyridinium and F is not D-Cit, D-Hci or a lower alkyl derivative of D-Cit or D-Hci;
G is Leu or Trp;
H is Lys(iPr), Gln, Met, or Arg;
I is Pro; and
J is Gly-NH
2
or D-Ala-NH
2
;
or a pharmaceutically acceptable salt thereof.
The invention also provides pharmaceutical compositions of the LHRH antagonist peptides.
In another aspect, the invention provides a method of inhibiting LHRH activity in a subject, comprising administering to a subject an effective amount of an LHRH antagonist, such that LHRH activity is inhibited.
In another aspect, the invention provides a method of inhibiting LHRH activity in a cell, comprising contacting a cell with an LHRH antagonist, such that LHRH activity is inhibited.
In another aspect, the invention provides a method of inhibiting growth of a hormone-dependent tumor in a subject, comprising administering to a subject an effective amount of an LHRH antagonist, such that tumor growth is inhibited.
In another aspect, the invention provides a method of inhibiting ovulation in a subject, comprising administering to a subject an effective amount of an LHRH antagonist, such that ovulation is inhibited.
In another aspect, the invention provides a packaged formulation for treating a subject for a disorder associated with LHRH activity, comprising an LHRH antagonist packaged with instructions for using the LHRH antagonist for treating a subject having a disorder associated with LHRH activity.
REFERENCES:
patent: 3787385 (1974-01-01), Folkers et al.
patent: 3953416 (1976-04-01), Folkers et al.
patent: 3974135 (1976-08-01), Folkers et al.
patent: 4215038 (1980-07-01), Rivier et al.
patent: 4244946 (1981-01-01), Rivier et al.
patent: 4292313 (1981-09-01), Vale, Jr. et al.
patent: 4307083 (1981-12-01), Rivier et al.
patent: 4377574 (1983-03-01), Rivier et al.
patent: 4386074 (1983-05-01), Vale, Jr. et al.
patent: 4444759 (1984-04-01), Rivier et al.
patent: 4489061 (1984-12-01), Rivier et al.
patent: 4504414 (1985-03-01), Folkers et al.
patent: 4547370 (1985-10-01), Roeske
patent: 4565804 (1986-01-01), Rivier et al.
patent: 4569927 (1986-02-01), Rivier et al.
patent: 4619914 (1986-10-01), Vale, Jr. et al.
patent: 4642332 (1987-02-01), Folkers et al.
patent: 4647653 (1987-03-01), Coy
patent: 4656247 (1987-04-01), Folkers et al.
patent: 4661472 (1987-04-01), Rivier et al.
patent: 4677193 (1987-06-01), Rivier et al.
patent: 4689396 (1987-08-01), Roeske et al.
patent: 4721775 (1988-01-01), Folkers et al.
patent: 4740500 (1988-04-01), Vale, Jr. et al.
patent: 4801577 (1989-01-01), Nestor, Jr. et al.
patent: 4851385 (1989-07-01), Roeske
patent: 4866160 (1989-09-01), Coy et al.
patent: 4935491 (1990-06-01), Folkers et al.
patent: 4992421 (1991-02-01), De et al.
patent: 5003011 (1991-03-01), Coy et al.
patent: 5064939 (1991-11-01), Rivier et al.
patent: 5073624 (1991-12-01), Coy et al.
patent: 5110904 (1992-05-01), Haviv et al.
patent: 5140009 (1992-08-01), Haviv et al.
patent: 5169932 (1992-12-01), Hoeger et al.
patent: 5171835 (1992-12-01), Janaky et al.
patent: 5180711 (1993-01-01), Hodgen
patent: 5296468 (1994-03-01), Hoeger et al.
patent: 5300492 (1994-04-01), Haviv et al.
patent: 5352796 (1994-10-01), Hoeger et al.
patent: 5371070 (1994-12-01), Koerber et al.
patent: 5413990 (1995-05-01), Haviv et al.
patent: 5470947 (1995-11-01), Folkers et al.
patent: 5843901 (1998-12-01), Roeske
patent: 0 328 090 (1989-08-01), None
patent: 2 329 294 (1977-05-01), None
patent: WO89/01944 (1989-03-01), None
patent: WO92/20711 (1992-11-01), None
patent: WO95/04540 (1995-02-01), None
Coy, D.H. et al., (1976), “Analogs of Luteinizing Hormone-Releasing Hormone with Increased Biological Activity Produced by D-Amino Acid Substitution at Position 6”,J. Med. Chem., 19, pp. 423-425.
Du, Y-C. “Peptides: Biology, Chemistry; Proc. 1992 Chinese Pept. Symp.” (1993), Tian, Z. et al. “Structure-activity Studies of LHRH Antagonists with Sidechain Modified D-Lys(6)” pp. 45-4
Borin Michael
DiConti Giulio A.
Indiana University Foundation
Laccotripe Maria C.
Lahive & Cockfield LLP
LandOfFree
Methods for treating disorders associated with LHRH activity does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods for treating disorders associated with LHRH activity, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods for treating disorders associated with LHRH activity will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2880510