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Details for Patent: 4,628,043

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Details for Patent: 4,628,043

Title: Hypothalamic GRF agonists
Abstract:Synthetic peptides are provided which are extremely potent in stimulating the release of pituitary GH in animals and which have the formula: H--R.sub.1 --Ala--Asp--Ala--Ile--Phe--Thr--R.sub.8 --Ser--R.sub.10 --Arg--R.sub.12 --R.sub.13 --Leu--R.sub.15 --Gln--Leu--R.sub.18 --Ala--Arg--Lys--Leu--Leu--R.sub.24 --R.sub.25 --Ile--R.sub.27 --R.sub.28 --Arg--Gln--Gln--Gly--Glu--R.sub.34 --Asn--Gln--Glu--R.sub.38 --R.sub.39 --R.sub.40 --Arg--R.sub.42 --R.sub.43 --Leu--Y wherein R.sub.1 is Tyr, Met, Leu, D--Tyr, D--His or His; R.sub.8 is Ser or Asn; R.sub.10 is Tyr or D--Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D--Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; and Y represents the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR,--CRO,--CONHNHR, --CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen, or a fragment thereof extending from the N-terminus in a continuous sequence at least to the residue in position 29, which fragment is biologically active to cause the release of GH from the pituitary, or a nontoxic salt of such peptide or peptide fragment. The peptides are analogs of human GRF and contain at least two but less than all of the following residues: R.sub.8 is Asn, R.sub.12 is Lys, R.sub.13 is Val, R.sub.18 is Ser, R.sub.24 is Gln, R.sub.25 is Asp, R.sub.28 is Ser.
Inventor(s): Spiess; Joachim (Encinitas, CA), Rivier; Jean E. F. (LaJolla, CA), Vale, Jr.; Wylie W. (LaJolla, CA)
Assignee: The Salk Institute for Biological Studies (San Diego, CA)
Filing Date:Mar 21, 1985
Application Number:06/714,687
Claims:1. A synthetic peptide having the formula: H--R.sub.1 --Ala--Asp--Ala--Ile--Phe--Thr--R.sub.8 --Ser--R.sub.10 --Arg--R.sub.12 --R.sub.13 --Leu--R.sub.15 --Gln--Leu--R.sub.18 --Ala--Arg--Lys--Leu--Leu--R.sub.24 --R.sub.25 --Ile--R.sub.27 --R.sub.28 --Arg--Gln--Gln--Gly--Glu--R.sub.34 --Asn--Gln--Glu--R.sub.38 --R.sub.39 --R.sub.40 --Arg--R.sub.42 --R.sub.43 --Leu--Y wherein R.sub.1 is Tyr, Met, Leu, D--Tyr, D--His or His; R.sub.8 is Ser or Asn; R.sub.10 is Tyr or D--Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D--Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; and Y represents the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR, --CRO, --CONHNHR, --CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen, provided however that at least two but not more than six of the following residues are present: R.sub.8 is Asn, R.sub.12 is Lys, R.sub.13 is Val, R.sub.18 is Ser, R.sub.24 is Gln, R.sub.25 is Asp, R.sub.28 is Ser, or a fragment thereof extending from the N-terminus in a continuous sequence at least to the residue in position 29, which fragment is biologically active to cause the release of GH from the pituitary, or a pharmaceutically acceptable nontoxic salt of such peptide or peptide fragment.

2. The peptide of claim 1 wherein Y is CONH.sub.2 or CONHR.

3. The peptide of claim 2 wherein R.sub.28 is Asn.

4. The peptide of claim 3 wherein R.sub.27 is Nle.

5. The peptide of claim 3 wherein R.sub.1 is His.

6. The peptide of claim 5 wherein R.sub.12 is Arg.

7. The peptide of claim 1 wherein R.sub.27 is Nle.

8. The peptide of claim 7 wherein R.sub.13 is Ile.

9. The peptide of claim 7 wherein R.sub.18 is Tyr.

10. The peptide of claim 1 wherein R.sub.8 is Ser.

11. The peptide of claim 1 wherein R.sub.18 is Tyr.

12. The peptide of claim 1 wherein R.sub.24 is His.

13. The peptide of claim 12 wherein R.sub.27 is Nle.

14. The peptide of claim 1 wherein R.sub.1 is Tyr, R.sub.8 is Asn, R.sub.10 is Tyr, R.sub.12 is Lys, R.sub.13 is Val, R.sub.15 is Gly, R.sub.18 is Ser, R.sub.24 is Gln, R.sub.25 is Asp, R.sub.27 is Nle, R.sub.28 is Asn and Y is --CONH.sub.2 or --CONHR.

15. The peptide of claim 1 having the formula: H--Tyr--Ala--Asp--Ala--Ile--Phe--Thr--Asn--Ser--Tyr--Arg--Lys--Val--Leu--G ly--Gln--Leu--Tyr--Ala--Arg--Lys--Leu--Leu--Gln--Asp--Ile--Nle--Asn--Arg--N H.sub.2.

16. A pharmaceutical composition for stimulating the release of GH in an animal comprising an effective amount of the peptide of claim 1 or a pharmaceutically acceptable nontoxic salt thereof, and a pharmaceutically or veterinarily acceptable liquid or solid carrier therefor.

17. A method of stimulating the release of growth hormone in an animal, which comprises administering to said animal an effective amount of a synthetic peptide having the formula: H--R.sub.1 --Ala--Asp--Ala--Ile--Phe--Thr--R.sub.8 --Ser--R.sub.10 --Arg--R.sub.12 --R.sub.13 --Leu--R.sub.15 --Gln--Leu--R.sub.18 --Ala--Arg--Lys--Leu--Leu--R.sub.24 --R.sub.25 --Ile--R.sub.27 --R.sub.28 --Arg--Gln--Gln--Gly--Glu--R.sub.34 --Asn--Gln--Glu--R.sub.38 --R.sub.39 --R.sub.40 --Arg--R.sub.42 --R.sub.43 --Leu--Y wherein R.sub.1 is Tyr, Met, Leu, D--Tyr, D--His or His; R.sub.8 is Ser or Asn; R.sub.10 is Tyr or D--Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.15 is Gly or D--Ala; R.sub.18 is Tyr or Ser; R.sub.24 is His or Gln; R.sub.25 is Glu or Asp; R.sub.27 is Met, Ala, Nle, Ile, Leu or Val; R.sub.28 is Asn or Ser; R.sub.34 is Arg or Ser; R.sub.38 is Gln or Arg; R.sub.39 is Arg or Gly; R.sub.40 is Ser or Ala; R.sub.42 is Phe or Ala; R.sub.43 is Asn or Arg; and Y represents the carboxyl moiety of the amino acid residue at the C-terminus and is the radical --COOR,--CRO,--CONHNHR, --CON(R)(R') or --CH.sub.2 OR, with R and R' being lower alkyl, fluoro lower alkyl or hydrogen, provided however that at least two but not more than six of the following residues are present: R.sub.8 is Asn, R.sub.12 is Lys, R.sub.13 is Val, R.sub.18 is Ser, R.sub.24 is Gln, R.sub.25 is Asp, R.sub.28 is Ser, or a fragment thereof extending from the N-terminus in a continuous sequence at least to the residue in position 29, which fragment is biologically active to cause the release of GH from the pituitary, or a pharmaceutically acceptable nontoxic salt of such peptide or peptide fragment.

18. A method in accordance with claim 17 wherein R.sub.1 is Tyr, R.sub.8 is Asn, R.sub.10 is Tyr, R.sub.12 is Lys, R.sub.13 is Val, R.sub.15 is Gly, R.sub.18 is Ser, R.sub.24 is Gln, R.sub.25 is Asp, R.sub.27 is Nle, R.sub.28 is Asn and Y is --CONH.sub.2 or CONHR.

19. A method in accordance with claim 17 wherein the peptide has the formula: H--Tyr--Ala--Asp--Ala--Ile--Phe--Thr--Asn--Ser--Tyr--Arg--Lys--Val--Leu--G ly--Gln--Leu--Ser--Ala--Arg--Lys--Leu--Leu--Gln--Asp--Ile--Nle--Asn--Arg--N H.sub.2.

20. A method for promotion of growth in warm-blooded nonhuman animals in accordance with claim 17.
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