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Details for Patent: 4,528,190

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Details for Patent: 4,528,190

Title: GRF Analogs IV
Abstract:Human GRF(hGRF), rat GRF(rGRF) porcine GRF(pGRF) and bovine GRF(bGRF) have been earlier characterized and synthesized. The invention provides synthetic peptides which are extremely potent in stimulating the release of pituitary GH in animals, including humans, which have resistance to enzymatic degradation in the body, and which have the sequence: R.sub.1 -R.sub.2 -R.sub.3 -Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -R.sub.14 -R.sub.15 -Gln-R.sub.17 -R.sub.18 -Ala-Arg-Lys-Leu-R.sub.23 -R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -R.sub.29 -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 -R.sub.44 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup..alpha. Me or N.sup..alpha. Me substitution or being unsubstituted; R.sub.2 is Ala, D-Ala or D-NMA; R.sub.3 is Asp or D-Asp; R.sub.8 is Ser, Asn, D-Ser or D-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.14 is Leu or D-Leu; R.sub.15 is Gly or D-Ala; R.sub.17 is Leu or D-Leu; R.sub.18 is Tyr or Ser; R.sub.23 is Leu or D-Leu; R.sub.24 is His or Gln; R.sub.25 is Glu, Asp, D-Glu or D-Asp; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn or Ser; R.sub.29 is Arg or D-Arg; 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, Ala or Val; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid; provided however that any or all of the residues between R.sub.28 and R.sub.44, inclusive, may be deleted and provided also that R.sub.2 is D-NMA and/or R.sub.14 is D-Leu and/or R.sub.29 is D-Arg. These peptides as well as their nontoxic salts may also be used diagnostically.
Inventor(s): Vale, Jr.; Wylie W. (La Jolla, CA), Rivier; Jean E. F. (La Jolla, CA)
Assignee: The Salk Institute For Biological Studies (San Diego, CA)
Filing Date:May 18, 1984
Application Number:06/611,844
Claims:1. A synthetic peptide, or a nontoxic salt thereof, having the sequence: R.sub.1 -R.sub.2 -R.sub.3 -Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -R.sub.14 -R.sub.15 -Gln-R.sub.17 -R.sub.18 -Ala-Arg-Lys-Leu-R.sub.23 -R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -R.sub.29 -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 -R.sub.44 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup..alpha. Me or N.sup..alpha. Me substitution or being unsubstituted; R.sub.2 is Ala, D-Ala or D-NMA; R.sub.3 is Asp or D-Asp; R.sub.8 is Ser, Asn, D-Ser or D-Asn; R.sub.1O is Tyr or D-Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.14 is Leu or D-Leu; R.sub.15 is Gly or D-Ala; R.sub.17 is Leu or D-Leu; R.sub.18 is Tyr or Ser; R.sub.23 is Leu or D-Leu; R.sub.24 is His or Gln; R.sub.25 is Glu, Asp, D-Glu or D-Asp; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn or Ser; R.sub.29 is Arg or D-Arg; 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, Ala or Val; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid; provided however that any or all of the residues between R.sub.28 and R.sub.44, inclusive, may be deleted and provided also that R.sub.2 is D-NMA or R.sub.14 is D-Leu or R.sub.29 is D-Arg.

2. The peptide of claim 1 wherein R.sub.2 is D-NMA.

3. The peptide of claim 1 wherein R.sub.29 is D-Arg.

4. The peptide of claim 1 wherein R.sub.14 is D-Leu.

5. The peptide of claim 1 wherein R.sub.25 is D-Glu.

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

7. The peptide of claim 1 wherein R.sub.17 is D-Leu.

8. The peptide of claim 1 wherein R.sub.25 is D-Asp.

9. The peptide of claim 1 wherein R.sub.1 is His, R.sub.3 is Asp, R.sub.8 is Ser, R.sub.10 is Tyr, R.sub.12 is Arg, R.sub.13 is Ile, R.sub.15 is Gly, R.sub.18 is Tyr, R.sub.24 is His, R.sub.28 is Asn, R.sub.34 is Arg, R.sub.38 is Gln, R.sub.39 is Arg, R.sub.40 is Ser, R.sub.42 is Phe, R.sub.43 is Asn and R.sub.44 is deleted.

10. The peptide of claim 9 wherein R.sub.17 is D-Leu, R.sub.23 is D-Leu, R.sub.25 is D-Glu, R.sub.27 is Nle and residues 30 through 44 are deleted.

11. The peptide of claim 2 wherein R.sub.3 is Asp, 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.28 is Ser, R.sub.34 is Ser, R.sub.38 is Arg, R.sub.39 is Gly, R.sub.40 is Ala, R.sub.42 is Ala, R.sub.43 is Arg and R.sub.44 is Leu.

12. The peptide of claim 11 wherein R.sub.17 is D-Leu, R.sub.23 is D-Leu, R.sub.25 is Asp, R.sub.27 is Nle and residues 30 through 44 are deleted.

13. The peptide of claim 2 wherein R.sub.14 is D-Leu.

14. The peptide of claim 2 wherein R.sub.29 is D-Arg.

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

16. A method for the therapeutic treatment of humans which comprises administering an effective amount of a compositon in accordance with claim 15.

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, or a nontoxic salt thereof, having the sequence: R.sub.1 -R.sub.2 -R.sub.3 -Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -R.sub.14 -R.sub.15 -Gln-R.sub.17 -R.sub.18 -Ala-Arg-Lys-Leu-R.sub.23 -R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -R.sub.29 -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 -R.sub.44 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup..alpha. Me or N.sup..alpha. Me substitution or being unsubstituted; R.sub.2 is Ala, D-Ala or D-NMA; R.sub.3 is Asp or D-Asp; R.sub.8 is Ser, Asn, D-Ser or D-Asn; R.sub.1O is Tyr or D-Tyr; R.sub.12 is Arg or Lys; R.sub.13 is Ile or Val; R.sub.14 is Leu or D-Leu; R.sub.15 is Gly or D-Ala; R.sub.17 is Leu or D-Leu; R.sub.18 is Tyr or Ser; R.sub.23 is Leu or D-Leu; R.sub.24 is His or Gln; R.sub.25 is Glu, Asp, D-Glu or D-Asp; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn or Ser; R.sub.29 is Arg or D-Arg; 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, Ala or Val; R.sub.43 is Asn or Arg; R.sub.44 is a natural amino acid; provided however that any or all of the residues between R.sub.28 and R.sub.44, inclusive, may be deleted and provided also that R.sub.2 is D-NMA or R.sub.14 is D-Leu or R.sub.29 is D-Arg.

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

19. A method for growth promotion in aquiculture by administering to fish or other cold-blooded animals in accordance with claim 17.

20. A method of accelerating growth in nonhuman animals, which method comprises administering an effective amount of a synthetic peptide having the sequence: R.sub.1 -R.sub.2 -R.sub.3 -Ala-Ile-Phe-Thr-R.sub.8 -Ser-R.sub.10 -Arg-R.sub.12 -R.sub.13 -R.sub.14 -R.sub.15 -Gln-R.sub.17 -R.sub.18 -Ala-Arg-Lys-Leu-R.sub.23 -R.sub.24 -R.sub.25 -Ile-R.sub.27 -R.sub.28 -R.sub.29 -NH.sub.2 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup..alpha. Me or N.sup..alpha. Me substitution; R.sub.2 is Ala, D-Ala or D-NMA; R.sub.3 is Asp or D-Asp; R.sub.8 is Ser, Asn, D-Ser or D-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.14 is Leu or D-Leu; R.sub.15 is Gly or D-Ala; R.sub.17 is Leu or D-Leu; R.sub.18 is Tyr or Ser; R.sub.23 is Leu or D-Leu; R.sub.24 is His or Gln; R.sub.25 is Glu, D-Glu, D-Asp or Asp; R.sub.27 is Met, D-Met, Ala, Nle, Ile, Leu, Nva or Val; R.sub.28 is Asn, Ser or des-R.sub.28 ; and R.sub.29 is Arg, D-Arg or des-R.sub.29 ; or a non toxic salt thereof.
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