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Generated: May 20, 2018

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Details for Patent: 4,728,726

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Title: GRF analogs IIIb
Abstract:Human GRF(hGRF), rat GRF(rGRF), porcine GRF(pGRF), ovine GRF(oGRF) 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 contain 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 -R.sub.30 -R.sub.31 -R.sub.32, wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup.a Me or N.sup.a 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, Ser or desR.sub.28 ; R.sub.29 is Arg, D-Arg or desR.sub.29 ; R.sub.30 is Gln or desR.sub.30 ; R.sub.31 is Glu or desR.sub.31 ; and R.sub.32 is Gly or desR.sub.32. These peptides as well as their nontoxic salts may also be used diagnostically.
Inventor(s): Rivier; Jean E. F. (La Jolla, CA), Vale, Jr.; Wylie W. (La Jolla, CA)
Assignee: The Salk Institute for Biological Studies (San Diego, CA)
Filing Date:Dec 08, 1986
Application Number:06/939,342
Claims:1. A synthetic peptide, or a nontoxic salt thereof, having the amino acid residue 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 -R.sub.30 -R.sub.31 -R.sub.32 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-Phe, Leu, His or D-His having either a C.sup.a Me or N.sup.a 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, Ser, D-Asn or desR.sub.28 ; R.sub.29 is Arg, D-Arg or DesR.sub.29 ; R.sub.30 is Gln or [desGln] desR.sub.30 ; R.sub.31 is Gln or DesR.sub.31 ; and R.sub.32 is Gly or desR.sub.32, provided however, that at least one of the following is present: R.sub.2 is D-NMA; R.sub.27 is Nle; R.sub.28 is D-Asn.

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

3. The peptide of claim 2 wherein R.sub.1 is an L-isomer.

4. The peptide of claim 3 wherein the carboxyl moiety at the C-terminus of said sequence is-CONHR wherein R is hydrogen or ethyl.

5. The peptide of claim 1 which is [Nle.sup.27 ]-hGRF(1-29)-NH.sub.2.

6. The peptide of claim 1 which is [D-Ala.sup.2, Nle.sup.27 ]-hGRF(1-29)-NH.sub.2.

7. The peptide of claim 1 which is [His.sup.1, N-NMA.sup.2, Nle.sup.27 ]-hGRF(1-29)NHEt.

8. A synthetic peptide, or a nontoxic salt thereof, having the amino acid residue 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-Nle-R.sub.28 -R.sub.29 -R.sub.30 -R.sub.31 -R.sub.32 wherein R.sub.1 is Tyr, D-Tyr, Met, Phe, D-Phe, pCl-phe, Leu, His or D-His having either a C.sup.a Me or N.sup.a 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 Gin; R.sub.25 is Glu, Asp, D-Glu or D-Asp; [R.sub.27 is Met, Ala, Nle, Ile, Leu, Nva or Val;] R.sub.28 is Asn or D-Asn; R.sub.29 is Arg or D-Arg; R.sub.30 is Gln or desR.sub.30 ; R.sub.31 is Gln or desR.sub.31 ; and R.sub.32 is Gly or desR.sub.32.

9. The peptide of claim 8 wherein R.sub.2 is D-NMA.

10. The peptide of claim 9 wherein R.sub.1 is an L-isomer.

11. The peptide of claim 10 wherein the carboxyl moiety at the C-terminus of said sequence is -13 CONHR and R is hydrogen or ethyl.

12. The peptide of claim 9 wherein R.sub.28 is Asn.

13. The peptide of claim 12 wherein R.sub.30 is desR.sub.30, R.sub.31 is desR.sub.31 and R.sub.32 is desR.sub.32.

14. The peptide of claim 8 wherein R.sub.2 is D-Ala.

15. The peptide of claim 14 wherein R.sub.1 is an L-isomer.

16. The peptide of claim 15 wherein the carboxyl moiety at the C-terminus of said sequence is --CONHR wherein R is hydrogen or ethyl.

17. The peptide of claim 16 wherein R.sub.28 is Asn.

18. The peptide of claim 17 wherein R.sub.30 is desR.sub.30, R.sub.31 is desR.sub.31 and R.sub.32 is desR.sub.32.

19. The peptide of claim 8 which is [D-Ala.sup.2, Nle.sup.27, Asn.sup.28 ]-hGRF(1-29)NHEt.

20. The peptide of claim 8 which is [D-NMA.sup.2, Nle.sup.27, Asn.sup.28 ]-hGRF(1-29)NHEt.

21. The peptide of claim 8 which is [D-NMA.sup.2, Nle.sup.27, Asn.sup.28 ]-hGRF(1-32)-NH.sub.2.

22. The peptide of claim 8 which is [D-NMA.sup.2, Nle.sup.27, Asn.sup.28 ]-hGRF(1-29)NH.sub.2.

23. The peptide of claim 8 which is [Nle.sup.27, D-Asn.sup.28 ]-rGRF(1-29)-NH.sub.2.

24. The peptide of claim 8 wherein R.sub.1 is substituted by N.sup.a Me.

25. The peptide of claim 11 wherein R.sub.1 is N.sup.a MeTyr.

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