US2015274798A1PendingUtilityA1

Novel gh-rh analogs with potent agonistic effects

41
Assignee: UNIV MIAMIPriority: Dec 21, 2011Filed: Jun 11, 2015Published: Oct 1, 2015
Est. expiryDec 21, 2031(~5.4 yrs left)· nominal 20-yr term from priority
Inventors:Andrew V. SchallyRen Zhi CaiMarta Zarandi
A61P 9/00A61P 43/00A61P 5/06C07K 14/60A61P 3/00A61K 38/00C07K 14/61
41
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Claims

Abstract

There are provided a novel series of peptide analogs of hGH-RH(1-29)NH 2 and hGH-RH(1-30)NH 2 which show high activities in stimulating the release of pituitary GH in animals. They retain their physiological activity in solution for extended periods of time and resist enzymic degradation in the body. These novel and useful properties appear to be due to novel substitution patterns ant at the 1, 15, 27 and 29 positions on the peptide.

Claims

exact text as granted — not AI-modified
What is claimed is: 
     
         1 . A GH-RH agonist peptide having the formula:
 [R 1 -A 1 , A 2 , A 6 , A 8 , A 11 , A 12 , A 15 , A 20 , A 21 , A 22 , Nle 27 , A 28 , Agm 29 ]hGH-RH(1-29)NH 2 ,   wherein   R 1  is Ac, Tfa, or is absent,   A 1  is Tyr, Dat, or N-Me-Tyr,   A 2  is Ala, D-Ala, Abu, or D-Abu,   A 6  is Phe or Fpa5,   A 8  is Asn, Ala, Gln, Thr, or N-Me-Ala,   A 11  is Arg, His, or Har,   A 12  is Orn, or Lys(Me) 2 ,   A 15  is His, Abu, Aib, Aah, Aap, Ala, or D-Ala   A 20  is Arg, His, or Har,   A 21  is Orn, or Lys(Me) 2 ,   A 22  is Leu, or Orn,   A 28  is Ser, or Asp,   and pharmaceutically acceptable salts thereof.   
     
     
         2 . The GH-RH agonist peptide of  claim 1 , wherein:
 R 1  is Ac or is absent,   A 1  is Tyr, Dat, or N-Me-Tyr,   A 2  is Ala, D-Ala, Abu, or D-Abu,   A 6  is Phe or Fpa5,   A 8  is Asn, Ala, Gln, or Thr,   A 12  is Orn,   A 15  is Abu,   A 21  is Orn,   A 28  is Ser, or Asp,   and pharmaceutically acceptable salts thereof.   
     
     
         3 . The GH-RH agonist peptide of  claim 1 , wherein:
 A 1  is Dat or N-Me-Tyr,   A 2  is Ala or D-Ala,   A 6  is Phe or Fpa5,   A 8  is Asn, Gln, or Thr,   A 12  is Orn,   A 15  is Abu,   A 21  is Orn,   A 28  is Ser, or Asp,   and pharmaceutically acceptable salts thereof.   
     
     
         4 . The GH-RH agonist peptide of  claim 1 , wherein the GH-RH agonist peptide is selected from the group consisting of:
 P-20103 [N-Me-Tyr 1 , Fpa5 6 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 2);   P-20105 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20107 [N-Me-Tyr 1 , Fpa5 6 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 3);   P-20109 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20110 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29);   P-20111 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20113 [N-Me-Tyr 1 , Fpa5 6 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 4);   P-20115 [N-Me-Tyr 1 , Fpa5 6 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 5);   P-20117 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29);   P-20350 [Dat 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20351 [Ac-N-Me-Tyr 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20356 [N-Me-Tyr 1 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 6);   P-20357 [Dat 1 , D-Ala 2 , N-Me-Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20358 [N-Me-Tyr 1 , D-Ala 2 , N-Me-Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20359 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20360 [N-Me-Tyr 1 , D-Ala 2 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20361 [N-Me-Tyr 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20367 [N-Me-Tyr 1 , D-Ala 2 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20370 [N-Me-Tyr 1 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 7);   P-20371 [N-Me-Tyr 1 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 8);   P-20372 [N-Me-Tyr 1 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 9);   P-20373 [N-Me-Tyr 1 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 10);   P-20374 [N-Me-Tyr 1 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 11);   P-20375 [N-Me-Tyr 1 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 12); and   P-20376 [N-Me-Tyr 1 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 13).   
     
     
         5 . The GH-RH agonist peptide of  claim 1 , wherein the GH-RH peptide is:
 P-20356 [N-Me-Tyr 1 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 6).   
     
     
         6 . The GH-RH agonist peptide of  claim 1 , wherein the GH-RH peptide is:
 P-20350 [Dat 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGHRH(1-29).   
     
     
         7 . The GH-RH agonist peptide of  claim 1 , wherein the GH-RH peptide is:
 P-20367 [N-Me-Tyr 1 , D-Ala 2 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGHRH(1-29).   
     
     
         8 . A pharmaceutical composition comprising a therapeutically effective amount of GH-RH agonist peptide having the formula:
 [R 1 -A 1 , A 2 , A 6 , A 8 , A 11 , A 12 , A 15 , A 20 , A 21 , A 22 , Nle 27 , A 28 , Agm 29 ]hGH-RH(1-29)NH 2 ,   wherein   R 1  is Ac, Tfa, or is absent,   A 1  is Tyr, Dat, or N-Me-Tyr,   A 2  is Ala, D-Ala, Abu, or D-Abu,   A 6  is Phe or Fpa5,   A 8  is Asn, Ala, Gln, Thr, or N-Me-Ala,   A 11  is Arg, His, or Har,   A 12  is Orn, or Lys(Me) 2 ,   A 15  is His, Abu, Aib, Aah, Aap, Ala, or D-Ala   A 20  is Arg, His, or Har,   A 21  is Orn, or Lys(Me) 2 ,   A 22  is Leu, or Orn,   A 28  is Ser, or Asp,   and pharmaceutical salts thereof, and a pharmaceutically acceptable excipient.   
     
     
         9 . The pharmaceutical composition of  claim 8 , wherein the GH-RH peptide is selected from the group consisting of:
 P-20103 [N-Me-Tyr 1 , Fpa5 6 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 2);   P-20105 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20107 [N-Me-Tyr 1 , Fpa5 6 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 3);   P-20109 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20110 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29);   P-20111 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20113 [N-Me-Tyr 1 , Fpa5 6 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 4);   P-20115 [N-Me-Tyr 1 , Fpa5 6 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 5);   P-20117 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29);   P-20350 [Dat 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20351 [Ac-N-Me-Tyr 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20356 [N-Me-Tyr 1 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 6);   P-20357 [Dat 1 , D-Ala 2 , N-Me-Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20358 [N-Me-Tyr 1 , D-Ala 2 , N-Me-Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20359 [N-Me-Tyr 1 , D-Ala 2 , Fpa5 6 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20360 [N-Me-Tyr 1 , D-Ala 2 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20361 [N-Me-Tyr 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20367 [N-Me-Tyr 1 , D-Ala 2 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29);   P-20370 [N-Me-Tyr 1 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 7);   P-20371 [N-Me-Tyr 1 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 8);   P-20372 [N-Me-Tyr 1 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 9);   P-20373 [N-Me-Tyr 1 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 10);   P-20374 [N-Me-Tyr 1 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 11);   P-20375 [N-Me-Tyr 1 , Thr 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 12); and   P-20376 [N-Me-Tyr 1 , Ala 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 13).   
     
     
         10 . The pharmaceutical composition of  claim 8 , wherein the GH-RH peptide is:
 P-20356 [N-Me-Tyr 1 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGH-RH(1-29) (SEQ ID NO: 6).   
     
     
         11 . The pharmaceutical composition of  claim 8 , wherein the GH-RH peptide is:
 P-20350 [Dat 1 , D-Ala 2 , Gln 8 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGHRH(1-29).   
     
     
         12 . The pharmaceutical composition of  claim 8 , wherein the GH-RH peptide is:
 P-20367 [N-Me-Tyr 1 , D-Ala 2 , Orn 12 , Abu 15 , Orn 21 , Nle 27 , Asp 28 , Agm 29 ]hGHRH(1-29).

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