Synthetic peptides having pituitary growth hormone releasing activity

• US 4,410,513 A
• Filed: 12/28/1981
• Issued: 10/18/1983
• Est. Priority Date: 12/28/1981
• Status: Expired due to Term

• Current Assignee: Smithkline Beecham Corporation (Smithkline Beecham PLC)
• Original Assignee: Beckman Instruments, Inc. (Danaher Corporation)
• Inventors: Momany, Frank A.
• Primary Examiner(s): Phillips, Delbert R.
• Assistant Examiner(s): Moezie, F. T.
• Application Number:
  US06/335,000
• Time in Patent Office: 659 Days
• Field of Search: 260/112.5 R
• US Class Current: 514/11.3
• 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: C07K 14/60 Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
• CPC Class Codes: Y10S 930/12 Growth hormone, growth factor other than t-cell or b-cell growth factor, and growth hormone releasing factor; related peptides

Abstract

Pentapeptides which act directly on the pituitary to release growth hormone therefrom.

Claims

1. A peptide having a formula ##STR72## wherein X₁, X₂, and X₃ are selected from a group consisting of N-terminal and desamino alpha-carbon substitutions;

a and b are 0 or 1, provided that a and b are 0 when A₁ is a desamino residue;

A₁ and A₄ are selected from a group consisting of His, Arg, Lys, α

-Naphth, β

-Naphth, Iql, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to A₁, the desamino forms thereof;

A₂ and A₅ are selected from a group consisting of D-His, D-Arg, D-Lys, D-α

-Naphth, D-β

-Naphth, D-Iql, D-Tyr, D-Trp, D-Phe, homologues and analogues thereof, and, with respect to A₅, the descarboxy forms thereof;

A₃ is selected from a group consisting of Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Gln, His, D-Ala, D-Val, D-Leu, D-Ile, D-Pro, D-Ser, D-Thr, D-Met, D-Asp, D-Glu, D-Asn, D-Gln, D-His, and homologues and analogues thereof; and

Y is selected from a group consisting of C-terminal and descarboxy alpha-carbon substitutions;

and the pharmaceutically acceptable salts thereof;

provided that, when (1) a is 1 and b is 0 and X₁ and X₂ are selected from the group consisting of --H and --CH₃ ;

(2) A₁ and A₄ are selected from the group consisting of Tyr, Trp, and Phe;

(3) A₃ is selected from the group consisting of Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Gln, and His; and

(4) Y is selected from the group consisting of --NR₁ R₂, --CH₂ OR, and --OR, wherein R, R₁, and R₂ are selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms;

then at least one of A₂ and A₅ is selected such that it is not from the group consisting of D-Tyr, D-Trp, D-Phe, and, with respect to A₅, the descarboxy forms thereof; and

when (1) a is 1 and b is 0 and X₁ and X₂ are selected from the group consisting of --H and --CH₃ ;

(2) A₂ and A₅ are selected from the group consisting of D-Tyr, D-Trp, D-Phe, and, with respect to A₅, the descarboxy forms thereof;

(3) A₃ is selected from the group consisting of Gly, Ala, Val, Leu, Ile, Pro, Ser, Thr, Met, Asp, Glu, Asn, Gln, and His; and

(4) Y is selected from the group consisting of --NR₁ R₂, --CH₂ OR, and --OR, wherein R, R₁, R₂ is selected from a group consisting of hydrogen and straight and branched chain alkyl groups containing 1-6 carbon atoms;

then at least one of A₁ and A₄ is selected such that it is not from a group consisting of Tyr, Trp, and Phe.

2. The peptide of claim 1 wherein:

a is 0 or 1 and b is 0;

X₁ and X₂ are selected from a group consisting of --R, --OR, and RC(O)--, wherein R is selected from a group consisting of hydrogen and straight and branched chain alkyl group containing 1-6 carbon atoms;

A₁ and A₄ are selected from the group consisting of His, Tyr, Trp, Phe, homologues and analogues thereof, and, with respect to A₁, the desamino forms thereof;

A₂ and A₅ are selected from the group consisting of D-His, D-Tyr, D-Trp, D-Phe, homologues and analogues thereof, and, with respect to A₅, the descarboxy form thereof;

A₃ is selected from the group consisting of Gly, Ala, Ser, Asn, Pro, D-Ala, D-Ser, D-Asn, D-Pro, and homologues and analogues thereof;

Y is selected from the group consisting of --CH₂ OH, --OR, and --NR₁ R₂, wherein R, R₁ and R₂ are selected from the group consisting of hydrogen and straight or branched chain alkyl group containing 1-6 carbon atoms; and

the pharmaceutically acceptable salts thereof.

3. The peptide of claim 1 having the formula ##STR73## wherein a is 0 or 1;

X₂ is selected from the group consisting of RCO and R-- wherein R is selected from the group consisting of hydrogen and alkyl groups containing 1-2 carbon atoms;

A₁ is selected from the group consisting of Tyr, O-Me-Tyr, His, 3-N-Me-His, p-Cl-Phe, and the desamino forms thereof;

A₃ is selected from the group consisting of Ala, Ser, and D-Ala;

A₄ is selected from the group consisting of Trp and Tyr;

A₅ is selected from the group consisting of D-Phe, D-His, D-Tyr, and D-p-Cl-Phe;

Y is selected from the group consisting of --OR, and --NHR, wherein R is selected from the group consisting of hydrogen and alkyl groups containing 1-2 carbon atoms; and

the pharmaceutically acceptable salts thereof.

4. The peptide of claim 1 of the formula H₂ -His-D-Trp-Ala-Trp-D-Phe-NH₂.

5. The peptide of claim 1 of the formula H₂ -Tyr-D-Trp-Ala-Trp-D-His-NH₂.

6. The peptide of claim 1 of the formula H₂ -His-D-Trp-Ala-Trp-D-His-NH₂.

7. The peptide of claim 1 of the formula H₂ -His-D-Trp-Ala-Trp-D-Tyr-NH₂.

8. The peptide of claim 1 of the formula H₂ -Tyr-D-Trp-Ala-Trp-D-p-Cl-Phe-NH₂.

9. The peptide of claim 1 of the formula H₂ -Tyr-D-Trp-D-Ala-Trp-D-Phe-NH₂.

10. The peptide of claim 1 of the formula H₂ -p-Cl-Phe-D-Trp-Ala-Trp-D-Phe-NH₂.

11. The peptide of claim 1 of the formula H-desaminoTyr-D-Trp-Ala-Trp-D-Phe-NH₂.

12. The peptide of claim 1 of the formula

CH₃ CO-Tyr-D-Trp-Ala-Trp-D-Phe-NH₂.

13. The peptide of claim 1 of the formula H₂ -O-Me-Tyr-D-Trp-Ala-Trp-D-Phe-NH₂.

14. A method of releasing growth hormone from a pituitary comprising contacting said pituitary with the peptide of claim 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13.

15. A method of releasing growth hormone in vivo from a pituitary comprising contacting said pituitary with the peptide of claim 4.