Chicken GNRH analogs and uses thereof in regulation of fertility and pregnancy

• US 6,323,179 B1
• Filed: 10/15/1999
• Issued: 11/27/2001
• Est. Priority Date: 10/15/1999
• Status: Expired due to Term

• Current Assignee: Theresa Siler-Khodr
• Original Assignee: Theresa Siler-Khodr
• Inventors: Siler-Khodr, Theresa
• Primary Examiner(s): Saoud, Christine J.
• Assistant Examiner(s): Chernyshev, Olga N.
• Application Number:
  US09/419,161
• Time in Patent Office: 774 Days
• Field of Search: 530/313, 530/328, 530/332, 530/333, 530/335, 514/2, 514/15, 930/21, 930/130
• US Class Current: 514/10.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61K 48/00 Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: C07K 7/23 Luteinising hormone-releasing hormone [LHRH]; Related peptides
• CPC Class Codes: Y10S 930/13 Luteinizing hormone-releasing hormone; related peptides

Abstract

Specially designed non-mammalian GnRH analog decapeptides resistant to degradation by the placental enzyme, C-ase-1, or a post-proline peptidase, are disclosed. The GnRH analogs are further defined as analogs of Chicken II GnRH or Salmon GnRH. These non-mammalian analogs incorporate D-arginine, D-leucine, D-tBu-Serine or D-Trp at position 6 and ethylamide or aza-Gly-amide at position 10. The D-Arg (6)-Chicken II GnRH-ethylamide, D-Arg (6)-Chicken II GnRH-aza-Gly (10)-amide, the D-Arg (6)-Salmon GnRH ethylamide, and D-Arg (6)-Salmon GnRH-aza-Gly (10)-amide analogs are also provided, and demonstrate preferential binding to chorionic GnRH receptor that is greater relative to the biding of these analogs to pituitary GnRH receptor. These non-mammalian GnRH analogs may be used in pharmaceutical preparation, and specifically in various treatment methods as a contraceptive or post-coital contraceptive agent. The non-mammalian GnRH analogs are also provided in pharmaceutical preparations that may be used clinically for maintaining pregnancy when used in very low doses and administered in pulsatile fashion. In another aspect, the non-mammalian GnRH analogs may be used a luteolytic agents. The aza-Gly (10) amide non-mammalian analogs are yet other embodiments of the non-mammalian GnRH analogs provided as a part of the invention.

Claims

1. A Chicken II GnRH decapeptide analog, having the sequence p-Glu-His-Trp-Ser-His-Xaa1-Trp-Tyr-Pro-Xaa2, capable of binding to human chorionic, placental or ovarian GnRH receptors and active in the presence of a post-proline peptidase or an endopeptidase, said analog comprising a D-amino acid substitution at position 6 and an ethylamide or aza-Gly-amide substitution at position 10.

2. The Chicken II GnRH decapeptide analog of claim 1 wherein the Chicken II GnRH analog is further defined as:

D-Arg(6)-Chicken II GnRH-ethylamide;

or

D-Arg(6)-Chicken II GnRH-aza-Gly(10)-amide.

3. The Chicken II GnRH decapeptide analog of claim 2 wherein the Chicken II GnRH analog is further defined as D-Arg(6)-Chicken II GnRH-aza-Gly(10)-amide having a sequence as defined in SEQ ID NO:

2 (p-Glu-His-Trp-Ser-His-D-Arg-Trp-Tyr-Pro-α

-aza-Gly-NH₂).

4. The Chicken II GnRH decapeptide analog of claim 3 wherein the Chicken II GnRH analog has a cDNA sequence of SEQ ID NO.1:

(CAG CAC TGG TCT CAT GGC TGG TAT CCT GGA).

5. A pharmaceutical preparation comprising a compound according to claim 3, in admixture with a pharmaceutically acceptable carrier, diluent or excipient.

6. The Chicken II GnRH decapeptide analog of claim 1 wherein the post-proline peptidase is chorionic peptidase-1.

7. The Chicken II GnRH decapeptide analog of claim 1 wherein the Chicken II GnRH analog is further defined as an aza-Gly(10)-amide GnRH analog.

8. The Chicken II GnRH decapeptide analog of claim 1 wherein the Chicken II GnRH analog is further defined as comprising a D-Arg, a D-Leu, D-tBu-serine, or a D-Trp substitution at position 6 and an aza-Gly amide or an ethylamide at position 10.