LHRH antagonist peptides

Abstract

Novel LHRH antagonist peptides, pharmaceutical compositions thereof, and methods of use thereof, are disclosed. The LHRH antagonist comprise a peptide compound, wherein a residue of the peptide compound corresponding to the amino acid at position 6 of natural mammalian LHRH comprises a hydrophilic N-acyl moiety, a dipolar moiety, a sulfonium moiety, a receptor-modifying moiety or a small polar moiety.

We claim:  
     
         1 . An LHRH antagonist comprising a peptide compound, wherein a residue of the peptide compound corresponding to the amino acid at position 6 of natural mammalian LHRH comprises D-Lys(Imdac), D-Lys(Ppic), D-Lys(Dodac), D-Lys(pGlu), D-Lys(Otac) and D-Lys(Onic) or a moiety selected from the group consisting of a dipolar moiety, a sulfonium moiety, a receptor-modifying moiet, and a small polar moiety, such that the peptide compound has LHRH antagonist activity, with the provisos that the dipolar moiety is not a zwitterionic pyridinium and the residue is not D-Cit, D-Hci or a lower alkyl derivative of D-Cit or D-Hci.  
     
     
         2 . The LHRH antagonist of  claim 1 , wherein the peptide compound comprises about 8 to about 12 residues.  
     
     
         3 . The LHRH antagonist of  claim 1 , wherein the peptide compound comprises 10 residues.  
     
     
         4 . A peptide compound comprising a structure: 
       A-B-C-D-E-F-G-H-I-J 
       wherein 
 A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar, or Ac-D-Pal;  
 B is His or 4-Cl-D-Phe;  
 C is Trp, D-Pal, D-Nal, L-Nal, D-Pal(N—O), or D-Trp;  
 D is Ser;  
 E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;  
 F is D-Lys(Imdac), D-Lys(Ppic), D-Lys(Dodac), D-Lys(pGlu), D-Lys(Otac), D-Lys(Onic) or a structure:  
                     
  wherein 
 R and X are, independently, H or alkyl; and  
 Y comprises a moiety selected from the group consisting a dipolar moiety, a sulfonium moiety, a receptor-modifying moiety and a small polar moiety, the provisos that the dipolar moiety is not a zwitterionic pyridinium and F is not D-Cit, D-Hci or a lower alkyl derivative of D-Cit or D-Hci;  
 
 G is Leu or Trp;  
 H is Lys(iPr), Gln, Met, or Arg;  
 I is Pro; and  
 J is Gly-NH 2  or D-Ala-NH 2 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         5 . The peptide compound of  claim 4 , wherein Y comprises a dipolar moiety, with the proviso that the dipolar moiety is not a zwitterionic pyridinium.  
     
     
         6 . The peptide compound of  claim 5 , wherein Y comprises a moiety selected from the group consisting of ylids, tertiary amine oxides, nitrile oxides and pyridine-N-oxides.  
     
     
         7 . The peptide compound of  claim 4 , wherein Y comprises a sulfonium moiety.  
     
     
         8 . The peptide compound of  claim 4 , wherein Y comprises a receptor-modifying moiety.  
     
     
         9 . The peptide compound of  claim 8 , wherein Y comprises a moiety selected from the group consisting of ylids, sulfonium moieties, α-halocarbonyls, sulfates, sulfonates, alkyl halides and benzyl halides.  
     
     
         10 . The peptide compound of  claim 9 , wherein Y comprises an α-halocarbonyl.  
     
     
         11 . The peptide compound of  claim 4 , wherein F is D-Lys(Imdac), D-Lys(Ppic) and D-Lys(Dodac), D-Lys(pGlu), D-Lys(Otac) or D-Lys(Onic).  
     
     
         12 . The peptide compound of  claim 2 , wherein Y comprises a small polar moiety, with the proviso that F is not D-Cit, D-Hci or a lower alkyl derivative of D-Cit or D-Hci.  
     
     
         13 . The peptide compound of  claim 12 , wherein F is selected from the group consisting of D-Asn, D-Gln and D-Thr.  
     
     
         14 . An LHRH antagonist comprising a peptide compound, wherein a residue of the peptide compound corresponding to the amino acid at position 6 of natural mammalian LHRH comprises a small polar moiety such that the peptide compound has LHRH antagonist activity, with the proviso that the residue is not D-Cit, D-Hci or a lower alkyl derivative of D-Cit or D-Hci.  
     
     
         15 . The LHRH antagonist of  claim 14 , wherein the antagonist has an antiovulatory activity of less than about 1 μg per rat in a rat antiovulation assay.  
     
     
         16 . The LHRH antagonist of  claim 14 , wherein the antagonist has an ED 50  in a histamine release assay of at least about 5 μg/ml.  
     
     
         17 . The LHRH antagonist of  claim 14 , wherein the peptide compound comprises about 8 to about 12 residues.  
     
     
         18 . The LHRH antagonist of  claim 14 , wherein the peptide compound comprises 10 residues.  
     
     
         19 . A peptide compound comprising a structure: 
       A-B-C-D-E-F-G-H-I-J 
       wherein 
 A is pyro-Glu, Ac-D-Nal , Ac-D-Qal, Ac-Sar, or Ac-D-Pal  
 B is His or 4-Cl-D-Phe  
 C is Trp, D-Pal, D-Nal, L-Nal, D-Pal(N—O), or D-Trp  
 D is Ser  
 E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;  
 F is  
                     
  wherein 
 R and X are, independently, H or alkyl; and  
 L comprises a small polar moiety, with the proviso that F is not D-Cit, D-Hci or a lower alkyl derivative of D-Cit or D-Hci;  
 
 G is Leu or Trp;  
 H is Lys(iPr), Gln, Met, or Arg  
 I is Pro; and  
 J is Gly-NH 2  or D-Ala-NH 2 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         20 . The peptide compound of  claim 19 , wherein F is selected from the group consisting of D-Asn, D-Gln and D-Thr.  
     
     
         21 . A peptide compound comprising a structure: 
       A-B-C-D-E-F-G-H-I-J 
       wherein 
 A is pyro-Glu, Ac-D-Nal, Ac-D-Qal, Ac-Sar, or Ac-D-Pal;  
 B is His or 4-Cl-D-Phe;  
 C is Trp, D-Pal, D-Nal, L-Nal, D-Pal(N—O), or D-Trp;  
 D is Ser;  
 E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;  
 F is D-Asn;  
 G is Leu or Trp;  
 H is Lys(iPr), Gln, Met, or Arg;  
 I is Pro; and  
 J is Gly-NH 2  or D-Ala-NH 2 ;  
 or a pharmaceutically acceptable salt thereof.  
 
     
     
         22 . A peptide compound comprising a structure: 
       A-B-C-D-E-F-G-H-I-J 
       wherein 
 A is pyro-Glu, Ac-D-Nal , Ac-D-Qal, Ac-Sar, or Ac-D-Pal;  
 B is His or 4-Cl-D-Phe;  
 C is Trp, D-Pal, D-Nal, L-Nal, D-Pal(N—O), or D-Trp;  
 D is Ser;  
 E is N-Me-Ala, Tyr, N-Me-Tyr, Ser, Lys(iPr), 4-Cl-Phe, His, Asn, Met, Ala, Arg or Ile;  
 F is D-Arg, D-Lys(iPr), D-Pal(iPr), D-Cit or Q, wherein Q has a structure  
                     
  wherein 
 R and X are, independently, H or alkyl; and  
 Z comprises a sulfonium moiety;  
 
 G is Leu or Trp;  
 H is Lys(iPr), Gln, Met, Arg or Q;  
 I is Pro; and  
 J is Gly-NH 2  or D-Ala-NH 2 ; 
 with the proviso that at least one of F and H is Q;  
 or a pharmaceutically acceptable salt thereof.  
 
 
     
     
         23 . A peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-Phe-D-Pal-Ser-Tyr-D-Pal(N—O)-Leu-Lys(iPr)-Pro-D-Ala-NH 2 . or a pharmaceutically acceptable salt thereof.    
     
     
         24 . A peptide compound comprising a structure 
 Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Pal(CH 2 COO − )-Leu-Lys(iPr)-Pro-D-Ala-NH 2 ; or a pharmaceutically acceptable salt thereof.    
     
     
         25 . A peptide compound comprising a structure 
 Ac-Sar-4-Cl-D-Phe-D-Nal-Ser-Tyr-D-Pal(Bzl)-Leu-Lys(iPr)-Pro-D-Ala-NH 2 ; or a pharmaceutically acceptable salt thereof.    
     
     
         26 . A peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-D-Phe-D-Trp-Ser-Tyr-D-Met(S + Me)-Leu-Arg-Pro-D-Ala-NH 2 ; or a pharmaceutically acceptable salt thereof.    
     
     
         27 . A peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Arg-Leu-Met(S + Me)-Pro-D-Ala-NH 2 ; or a pharmaceutically acceptable salt thereof.    
     
     
         28 . A peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Lys(Imdac)-Leu-Lys(iPr)-Pro-D-Ala-NH 2 ; or a pharmaceutically acceptable salt thereof.    
     
     
         29 . A peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-N-Me-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH 2 ; or a pharmaceutically acceptable salt thereof.    
     
     
         30 . A peptide compound comprising a structure: 
 Ac-D-Nal-4-Cl-D-Phe-D-Pal-Ser-Tyr-D-Asn-Leu-Lys(iPr)-Pro-D-Ala-NH 2 ; or a pharmaceutically acceptable salt thereof.    
     
     
         31 . A peptide compound comprising a structure selected from the group consisting of: 
 Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Gln 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Asn 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Thr 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 , Pip 9 -D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(Taurine) 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 , Pip 9 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Phe(4-NO 2 ) 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 , ProNHEt 9 -des-Gly 10 -LHRH    Ac-D-(or L)-9-anthryl-Ala 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-L-(or D)-9-anthryl-Ala 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-(or L)-Ada-Ala 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-L-(or D)-Ada-Ala 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(Glc) 6 -Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Pal(1-Bu) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Pal(Bzl) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Pal 5 , D-Pal(iPr) 6 , Lys(ipr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Cit 5 , D-Cit 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Pal 5 , D-Cit 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Cit 5 , D-Pal 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Asn 4 , Tyr 5 , D-Cit 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Cit 5 , D-Pal(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-HomoArg(NO 2 ) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(Glycolyl) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(iPrPic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(HomoPro) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Pal(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(3-pyridineacetic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(2-ClNic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-N α Me-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Cit 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(Otac) 5 , D-Lys(Otac) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(ONic) 5 , D-Lys(ONic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(Pyz) 5 ,D-Lys(Pyz) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(Gulonyl) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(iPrNic) 5 , D-Lys(iPrNic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(ONic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(OTac) 6 , Lys(ipr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(Pyz) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(nBuNic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(Amp) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(Dea) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(pGlu) 5 , D-Lys(pGlu) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , N α Me-Tyr 5 , D-Pal(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , C α Me-4Cl-Phe 2 , D-Pal 3 , N α Me-Tyr 5 , D-Pal(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(CNa) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(PEG) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(Oxa) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(CNa) 5 , D-Lys(CNa) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(ClNic) 5 , D-Lys(CINic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(Ac) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(Tris) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Gln(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(CSer) 6 , Lys(ipr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(Mop) 6 , Lys(ipr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys 5 , D-Pal(ipr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(Nic) 5 , D-Pal(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(Ac) 5 , D-Pal(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Glu(DEGA) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(Nic) 5 , D-Pal(Bzl) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(Ac) 5 , D-Pal(Bzj) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(TFAc) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys 5 , D-Pal(Bzl) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(iPr) 5 , D-Lys(Nic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(iPr) 5 , D-Lys(Pic) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(TFAc) 5 , D-Lys(TFAc) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(iPr) 5 , 4-Cl-D-Phe 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(iPr) 5 , D-Nal 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(iPr) 5 , D-Lys(pGlu) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(iPr) 5 , D-Lys(OTac) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Ile 5 , D-Pal(Bzl) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , Lys(Pic) 5 , D-Pal(iPr) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 , 4-Cl-D-Phe 2 , D-Pal 3 , D-Lys(3-α-Pro) 6 , Lys(iPr) 8 , D-Ala 10 -LHRH-TFA    Ac-D-Nal-4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Ser) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(pGlu) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Ac) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Imdac) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Dodac) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Ser 5 ,D-Pal(iPr) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(iPr) 5 , D-Lys(TFAC) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,His 5 D-Pal(iPr) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Asn 5 ,D-Pal(ipr) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Lys(iPr) 5 ,D-Lys(4HBc) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Met 5 ,D-Pal(iPr) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Phe 2 ,D-Pal 3 ,Ala 5 ,D-Pal(iPr) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,N-Me-Ala 5 , D-Pal(iPr) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Hippic) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(AcGly) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Ppic) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Mts) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Orotic) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-Sar 1 ,4-Cl-D-Phe 2 ,D-Nal 3 ,D-Pal(Bzl) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-Sar 1 ,4-Cl-D-Phe 2 ,1-1-Nal 3 ,D-Pal(Bzl) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Pal(CH 2 COOH) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Ala) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-Sar 1 ,4-Cl-D-Phe 2 ,D-1-Nal 3 ,D-Pal(iPr) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-Sar 1 ,4-Cl-D-Phe 2 ,L-1-Nal 3 ,D-Pal(ipr) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Gulonyl) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Pal(N—O) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Ppic) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Imdac) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-phe 2 ,D-Pal 3 ,D-Lys(Onic) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Qal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Otac) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(Dodac) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Pal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Pal(iPr) 6 , Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,N-Me-Tyr 5 ,D-Asn 6 ,Lys(iPr)8,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,N-Me-Tyr 5 ,D-Lys(Onic) 8 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,N-Me-Tyr 5 ,D-Lys(Ac) 6 ,Lys(ipr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Lys(iPr) 5 ,D-His 6 ,Trp 7 ,Orn 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,His 5 ,D-Arg 6 , Trp 7 ,Orn 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Arg 5 ,D-His 6 , Trp 7 ,Orn 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,Lys(iPr) 5 ,D-Trp 6 ,Trp 7 ,Orn 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,4-Cl-Phe 5 , D-Pal(iPr) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal(N—O) 3 ,D-Pal(iPr) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Arg 6 , Met 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Arg 6 , Met(S + Me) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Met 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Met(S + Me) 6 , D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Arg 6 , Lys(COCH 2 Br) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Met(S + Me) 6 , Met(S + Me) 8 ,D-Ala 10 -LHRH    Met(S + Me) 8 -LHRH    Lys(COCH 2 Br) 8 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Lys(COCH 2 Br) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(COCH 2 CH 2 N(Et) 2 ) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(2-pyrimidylthio)acetic) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Met(S + CH 2 C H 5 ) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 , D-Met(S + CH 3 ) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Met(S + CH 2 COPh) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Dap(COCH 2 S + Me 2 ) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,His 5 D-Pal(iPr) 6 ,Lys(iPr) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Arg 6 , Met(S + Me) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Trp 3 ,D-Met(S + CH 2 —CH═CH 2 ) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pad 3 ,D-Arg 6 , Orn(COCH 2 S + Me 2 ) 8 ,D-Ala 10 ,LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Arg 6 , Orn(COCH 2 SMe) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Arg 6 ,Met 8 , D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Lys(COCH 2 S + Me 2 ) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Arg 6 , Lys(COCH 2 S + Me 2 ) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Met(S + Me) 6 , Met(S + Me) 8 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Orn(COCH 2 S + Me 2 ) 6 ,D-Ala 10 -LHRH    Ac-D-Nal 1 ,4-Cl-D-Phe 2 ,D-Pal 3 ,D-Arg 6 ,Dap(COCH 2 S + Me 2 ) 8 ,D-Ala 10 -LHRH and pharmaceutically acceptable salts thereof.    
     
     
         32 . A pharmaceutical composition comprising a peptide compound of claim  1 - 31  and a pharmaceutically acceptable carrier.  
     
     
         33 . A method of inhibiting LHRH activity in a subject, comprising administering to a subject an effective amount of a peptide compound of claim  1 - 31 , such that LHRH activity is inhibited.  
     
     
         34 . A method of inhibiting growth of a hormone-dependent tumor in a subject, comprising administering to a subject an effective amount of a peptide compound of claim  1 - 31 , such that growth of the hormone-dependent tumor is inhibited.  
     
     
         35 . The method of  claim 34 , wherein the hormone-dependent tumor is a prostate tumor.  
     
     
         36 . A method of inhibiting ovulation in a subject, comprising administering to a subject an effective amount of a peptide compound of claim  1 - 31 , such that ovulation is inhibited.  
     
     
         37 . A packaged formulation for treating a subject for a disorder associated with LHRH activity, comprising the peptide compound of claim  1 - 31  packaged with instructions for using the LHRH antagonist for treating a subject having a disorder associated with LHRH activity.  
     
     
         38 . A pharmaceutical composition comprising the peptide compound of  claim 29  and a pharmaceutically acceptable carrier.  
     
     
         39 . The pharmaceutical composition of  claim 38 , which comprises a slow release polymer.  
     
     
         40 . The pharmaceutical composition of  claim 38 , which is suitable for depot injection.  
     
     
         41 . A method of inhibiting LHRH activity in a subject, comprising administering to a subject an effective amount of the peptide compound of  claim 29 , such that LHRH activity is inhibited.  
     
     
         42 . A method of inhibiting growth of a hormone-dependent tumor in a subject, comprising administering to a subject an effective amount of the peptide compound of  claim 29 , such that growth of the hormone-dependent tumor is inhibited.  
     
     
         43 . The method of  claim 42 , wherein the hormone-dependent tumor is a prostate tumor.  
     
     
         44 . A packaged formulation for treating a subject for a disorder associated with LHRH activity, comprising the peptide compound of  claim 29  packaged with instructions for using the LHRH antagonist for treating a subject having a disorder associated with LHRH activity.  
     
     
         45 . Use of the peptide compound of claim  1 - 31  in the manufacture of a medicament for the treatment of a disorder selected from the group consisting of precocious puberty, prostate cancer, ovarian cancer, benign prostatic hypertrophy, endometriosis, uterine fibroids, breast cancer, premenstrual syndrome, polycystic ovary syndrome, and diseases which result from excesses of gonadal hormones.  
     
     
         46 . Use of the peptide of  claim 29  in the manufacture of a medicament for the treatment of a disorder selected from the group consisting of precocious puberty, prostate cancer, ovarian cancer, benign prostatic hypertrophy, endometriosis, uterine fibroids, breast cancer, premenstrual syndrome, polycystic ovary syndrome, and diseases which result from excesses of gonadal hormones.  
     
     
         47 . The use of  claim 46 , wherein the disorder is prostate cancer.