Analogs of parathyroid hormone
View Patent ↗The present invention is directed to peptide analogues of fragment of parathyroid hormone (PTH) or parathyroid hormone-related protein (PTHrP), a method of using said analogues alone or in combination with a bisphosphonate or calcitonin to treat osteoporosis and pharmaceutical compositions comprising said analogues alone or in combination with a bisphosphonate or calcitonin.
1. A peptide of formula (I):
wherein
A 1 is Ser, Ala, or Dap;
A 3 is Ser, Thr, or Aib;
A 5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe, in which X is OH, a halogen, or CH 3 ;
A 7 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 8 is Met, Nva, Leu, Val, Ile, Cha, Acc or Nle;
A 11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 12 is Gly, Acc or Aib;
A 15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, ACC, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 16 is Ser, Asn, Ala, or Aib;
A 17 is Ser, Thr, or Aib;
A 18 is Met, Nva, Leu, Val, Ile, Nle, Acc, Cha, or Aib;
A 19 is Glu or Aib;
A 21 is Val, Acc, Cha, or Met;
A 22 is Acc or Glu;
A 23 is Trp, Acc, or Cha;
A 24 is Leu, Acc, or Cha;
A 27 is Lys, Aib, Leu, hArg, Gln, Acc, or Cha;
A 28 is Leu, Acc, or Cha;
A 29 is Gln;
A 30 is Asp or Lys;
A 31 is Val, Leu, Nle, Acc, Cha, or deleted;
A 32 is His or deleted;
A 33 is Asn or deleted;
A 34 is Phe, Tyr, Amp, Aib, or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 7-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxy-phenylalkyl, or C 11-120 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H, or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 12 , A 15 , A 18 , A 21 , A 22 , A 23 , A 24 , A 27 , A 28 , and A 31 is Acc; or a pharmaceutically acceptable salt thereof.
2. A peptide of claim 1 , wherein
A 3 is Ser;
A 5 is Ile or Acc;
A 7 is Leu, Acc, or Cha;
A 8 is Acc, Met, Nva, Leu, Val, Ile, or Nle;
A 11 is Leu, Acc, or Cha;
A 12 is Acc or Gly;
A 15 is Leu, Acc, or Cha;
A 16 is Asn or Aib;
A 17 is Ser or Aib;
A 18 is Acc, Met, or Nle;
A 21 is Val or Acc;
A 27 is Lys, hArg, Acc, or Cha;
A 31 is Val, Leu, Nle, Acc, or Cha;
A 32 is His;
A 33 is Asn;
A 34 is Phe, Tyr, Amp, or Aib;
or a pharmaceutically acceptable salt thereof.
3. A peptide of claim 2 , wherein
A 5 is Ile or Ahc;
A 7 is Leu, Ahc, or Cha;
A 8 is Ahc, Met, or Nle;
A 11 is Leu, Ahc, or Cha;
A 12 is Ahc or Gly;
A 15 is Leu, Ahc, or Cha;
A 18 is Met or Ahc;
A 21 is Val or Ahc;
A 22 is Glu or Ahc;
A 23 is Trp, Ahc, or Cha;
A 24 is Leu, Ahc, or Cha;
A 27 is Lys, hArg, Ahc, or Cha;
A 28 is Leu, Ahc, or Cha;
A 31 is Val, Leu, Nle, Ahc, or Cha;
R 1 is H;
R 2 is H; and
R 3 is NH 2 ;
or a pharmaceutically acceptable salt thereof.
4. A peptide of claim 3 , wherein at least one of A 7 , A 11 , A 15 , A 23 , A 24 , A 27 , A 28 , or A 31 is Cha.
5. A peptide of claim 3 , wherein at least one of A 16 , A 17 , A 19 , or A 34 is Aib.
6. A peptide of the formula; [Cha 22,23 , Glu 25 , Lys 26,30 , Leu 28 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Cha 22,23 , Glu 25 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28,31 , Lys 26 , Aib 29 , Nle 30 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28,30,31 , Lys 26 , Aib 29 ]hPTHrP(1-34)NH 2 , ]Glu 22,25,29 , Leu 23,28,30,31 , Lys 26 ]hPTHrP(1-34)NH 2 ; [Glu 22,25,28 , Leu 23,28,31 , Lys 26 , Nle 30 ]hPTHrP(1-34)NH 2 ; [Ser 1 , Ile 5 , Met 8 , Asn 10 , Leu 11,23,28,31 , His 14 , Cha 15 , Glu 22,25 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Cha 23 , Lys 26 , Leu 28,31 , Aib 29 , Nle 30 ]hPTHrP(1-34)NH 2 , [Cha 22,23 , Glu 25 , Lys 26,30 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28,31 , Glu 25,29 , Lys 26 , Nle 30 ]hPTHrP(1-34)NH 2 ; [Cha 7,11,15 ]hPTHrP(1-34)NH 2 ; [Cha 7,8,15 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Cha 23 , Aib 25,29 , Lys 26,30 , Leu 28,31 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Cha 23 , Aib 25,29 , Lys 26 , Leu 28 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Aib 25,29 , Lys 26 ]hPTHrP(1-34)NH 2 ; [Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Cha 23 , Lys 26 , Leu 28,31 , Aib 29 , Nle 30 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Cha 23 , Lys 26,30 , Aib 29 , Leu 31 ]hPTHrP(1-34)NH 2 ; [Glu 22,25, Leu 23,28,31 , Lys 26 , Aib 29,31 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28,31 , Lys 26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28,31 , Aib 26,29 , Lys 30 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Cha 23 , Lys 26,30 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Cha 23 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Cha 23 , Lys26,30, Leu 28 , Aib 29 ]hPTHrP(1-34)NH 2 ; or [Leu 27 , Aib 29 ]hPTHrP(1-34)NH 2 ; or a pharmaceutically acceptable salt thereof.
7. A peptide of the formula: [Glu 22,25 , Leu 23,28,31 , Lys 26 , Ahc 27 , Aib 29 , Nle 30 ]hPTHrP(1-34)NH 2 ; [Ser 1 , Ile 5 , Cha 7,11 , Met 8 , Asn 10, His 14 , Glu 22,25 , Leu 23,28,31 , Lys 26,30 , Ahc 27 , Aib 29 ]hPTHrP(1-34)NH 2 ; (Ser 1 , Ile 5 , Met 8 , Asn 10 , Leu 11,23,28,31 , His 14 , Cha 15 , Glu 22,25 , Lys 26,30 , Ahc 27 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Ahc 23 , Aib 25,29 , Lys 26,30 , Leu 28,31 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28,31 , Lys 26,30 , Ahc 29 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28,31 , Ahc 24 , Glu 25 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28,31 , Ahc 24,27 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22,24,27 , Leu 23,28,31 , Glu 25 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28,31 , Aib 25,29 , Lys 26,30 , Ahc 27 ]hPTHrP(1-34)NH 2 ; [Ahc 22,27 , Leu 23,28,31 , Aib 25,29 , Lys 26,30 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,31 , Ahc 24,27 , Lys 25,26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Ahc 24,27 , Lys 25,26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Cha 23 , Ahc 24,27 , Lys 25,26,30 , Leu 28 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Cha 23 , Ahc 24,27 , Lys 25,26,30 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Cha 23 , Ahc 24,27 , Lys 25,26,30 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,31 , Ahc 24,27 , Lys 25,26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Ahc 24,27 , Lys 25,26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Cha 23 , Ahc , Lys 25,26 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Cha 23 , Ahc 24,27 , Lys 25,26 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Lys 25,26 , Ahc 27 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,31 , Lys 25,26, Ahc 27 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,31 , Lys 25,26,30 , Ahc 27 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Lys 25,26,30 , Ahc 27 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28,31 , Lys 26 , Aib 29 , Ahc 30 ]hPTHrP(1-34)NH 2 ; [Aib 22,29 , Leu 23,28,31 , Glu 25 , Lys 26,30 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Ahc 23 , Glu 25,29 , Lys 26,30 , Leu 26,31 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28,31 , Ahc 24 , Glu 25,29 , Lys 26,30 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28,31 , Glu 25,29 , Lys 26,30 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28,31 , Glu 25,29 , Lys 26,30 , Ahc 27 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,31 , Glu 25,29 , Lys 26,30 , Ahc 28 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28,31 , Glu 25,29 , Lys 26 , Ahc 30 ]hPTHrP(1-34)NH 2 ; [Cha 22 , Leu 23,28 , Glu 25,29 , Lys 26,30 , Ahc 31 ]hPTHrP(1-34)NH 2 ; [Glu 22,29 , Ahc 23 , Aib 25 , Lys 26,30 , Leu 28,31 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Leu 23,28,31 , Aib 25 , Lys 26,30 , Glu 29 ]hPTHrP(1-34)NH 2 ; (Glu 22,29 , Leu 23,28,31 , Ahc 24 , Aib 25 , Lys 26,30 ]hPTHrP(1-34)NH 2 ; [Glu 22,29 , Leu 23,31 , Aib 25 , Lys 26,30 , Ahc 28 ]hPTHrP(1-34)NH 2 ; [Glu 22,29 , Leu 23,28 , Aib 25 , Lys 26,30 , Ahc 31 ]hPTHrP(1-34)NH 2 ; [Glu 22,25,29 , Leu 23,28,31 , Aib 25 , Lys 26 , Ahc 30 ]hPTHrP(1-34)NH 2 ; [Glu 22,25,29 , Leu 23,28,31 , Lys 26 , Ahc 27 , Aib 30 ]hPTHrP(1-34)NH 2 ; [Glu 22,25,29 , Leu 23,28,31 , Ahc 24 , Lys 26 , Aib 30 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Leu 23,28,31 , Glu 25,29 , Lys 26 , Aib 30 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Leu 23,28 , Glu 25,29 , Lys 26,30,31 ]hPTHrP(1-34)NH 2 ; [Glu 22,25,29 , Leu 23,28 , Lys 26,31 , Ahc 30 ]hPTHrP(1- 34 )NH 2 ; [Glu 22,25,29 , Leu 23,28 , Lys 26,30,31 , Ahc 27 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Cha 23 , Glu 25 , Lys 26,30 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Cha 23 , Lys 25,26,30 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Cha 23 , Lys 25,26 , Leu 28,31 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Leu 23,28 , Lys 25,26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22 , Leu 23,28 , Arg 25 , Lys 26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22,24 , Leu 23,28,31 , Glu 25 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22,24 , Leu 23,28,31 , Lys 25,26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22,24 , Leu 23,28,31 , Lys 25,26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Ahc 22,24 , Leu 23,28 , Lys 25,26 , Aib29]hPTHrP(1-34)NH 2 ; [Ahc 22,24 , Leu 23,28 , Arg 25 , Lys 26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Lys 23,28,31 , Ahc 24 , Lys 25,26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,1 , Ahc 24 , Lys 25,26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Ahc 24 , Lys 25,26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,31 , Ahc 24 , Arg 25 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,31 , Ahc 24 , Arg 25 , Lys 26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Ahc 24 , Arg 25 , Lys 26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Ahc 23 , Aib 25,29 , Lys 26,30 , Leu 28,31 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Ahc 23 , Aib 25,29 Lys 26 , Leu 28 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Ahc 23,31 , Aib 25,29 , Lys 26 , Leu 28 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Aib 25,29 , Lys 26,30 , Ahc 31 ]hPTHrP(1-34)NH 2 ; [Glu 2 , Leu 23,28 , Aib 25,29 , Lys 26 , Ahc 13 ]hPTHrP(1-34)NH 2 ; [Glu 22,25 , Leu 23,28 , Ahc 24,31 , Lys 26,30 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28 , Ahc 24,31 , Lys 25,26 , Aib 29 ]hPTHrP(1-34)NH 2 ; [Glu 22 , Leu 23,28,31 , Ahc 24 , Aib 25,29 , Lys 26,30 , ]hPTHrP(1-34)NH 2 ; or a pharmaceutically acceptable salt thereof.
8. A peptide of formula (II):
wherein
A 1 is Ser, Ala, or Dap;
A 3 is Ser, Thr, or Aib;
A 5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH 3 ;
A 7 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A 11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 12 is Gly or Aib;
A 15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 16 is Ser, Asn, Ala, or Aib;
A 17 is Ser, Thr, or Aib;
A 18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A 19 is Glu or Aib;
A 21 is Val, Cha, or Met;
A 23 is Trp or Cha;
A 24 is Leu or Cha;
A 27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A 28 is Leu or Cha;
A 30 is Asp or Lys;
A 31 is Val, Nle, Cha, or deleted;
A 32 is His or deleted;
A 33 is Asn or deleted;
A 34 is Phe, Tyr, Amp, Aib, or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxy-phenylalkyl, or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—C 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H, or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 15 , A 18 , A 21 , A 23 , A 24 , A 27 , A 28 , and A 31 is Cha, or at least one of A 3 , A 12 , A 16 , A 17 , A 18 , A 19 , and A 34 is Aib; or a pharmaceutically acceptable salt thereof;
provided that if A 12 is Gly, then at least one of A 5 is Leu, Nle, β-Nal, Trp, Pal, Phe or p-X-Phe; A 15 is Nle, Ile, β-Nal, Trp, Pal, Phe, or p-X-Phe; A 7 is Ile; or A 11 is Ile or Pal;
provided that if A 12 is Aib and A 1 is Dap, then at least one of A 5 is Leu, Nle, β-Nal, Trp, Pal, Phe or p-X-Phe; A 7 is Ile; A 11 is Ile or Pal; or A 15 is Nle, Ile, β-Nal, Trp, Pal, Phe, or p-X-Phe; and further
provided that the peptide is not [Aib 12 , Tyr 34 ]hPTH(1-34)NH 2 or [Cha 8 ]hPTH(1-34)NH 2 .
9. A peptide of claim 8 wherein at least one of A 7 , A 11 , A 15 , A 23 , A 24 , A 27 , A 28 , and A 31 is Cha; or a pharmaceutically acceptable salt thereof.
10. A peptide of claim 9 , wherein
A 3 is Ser;
A 5 is Ile;
A 7 is Leu or Cha;
A 8 is Met, Nva, Leu, Val, Ile, or Nle;
A 11 is Leu or Cha;
A 12 is Gly;
A 15 is Leu or Cha;
A 16 is Asn or Aib;
A 17 is Ser;
A 18 is Met or Nle;
A 21 is Val;
A 27 is Lys, hArg, or Cha;
A 32 is His;
A 31 is Val, Nle, or Cha;
A 33 is Asn;
A 34 is Phe, Tyr, Amp, or Aib;
R 1 is H;
R 2 is H; and
R 3 is NH 2 ;
or a pharmaceutically acceptable salt thereof.
11. A peptide of claim 10 , wherein at least one of A 7 and A 11 is Cha; or a pharmaceutically acceptable salt thereof.
12. A peptide of the formula: [Cha 7,11,15 ]hPTH(1-34)NH 2 ; or a pharmaceutically acceptable salt thereof.
13. A peptide of claim 10 , wherein at least one of A 15 , A 23 , A 24 , A 27 , A 28 , and A 31 is Cha; or a pharmaceutically acceptable salt thereof.
14. A peptide of claim 8 , wherein at least one of A 3 , A 12 , A 16 , A 17 , A 18 , A 19 and A 34 is Aib; or a pharmaceutically acceptable salt thereof.
15. A peptide of claim 14 , wherein
A 3 is Ser or Aib;
A 5 is Ile;
A 7 is Leu or Cha;
A 8 is Met, Nva, Leu, Val, Ile, or Nle;
A 11 is Leu or Cha;
A 15 is Leu or Cha;
A 16 is Asn or Aib;
A 18 is Met, Aib, or Nle;
A 21 is Val;
A 27 is Lys, Aib, Leu, hArg, or Cha;
A 31 is Val, Nle, or Cha;
A 32 is His;
A 33 is Asn;
A 34 is Phe, Tyr, Amp, or Aib;
R 1 is H;
R 2 is H; and
R 3 is NH 2 ;
or a pharmaceutically acceptable salt thereof.
16. A peptide of claim 9 , wherein at least one of A 3 , A 12 , A 16 , A 17 , A 19 , and A 34 is Aib; or a pharmaceutically acceptable salt thereof.
17. A peptide of the formula: [Aib 17 ]hPTH(1-34)NH 2 or [Aib 12 ]hPTH(1-34)NH 2 ; or a pharmaceutically acceptable salt thereof.
18. A peptide of claim 8 wherein at least one of A 7 , A 11 , A 15 , A 23 , A 24 , A 27 , A 28 , and A 31 is Cha and at least one of A 3 , A 12 , A 16 , A 17 , A 18 , A 19 , and A 34 is Aib; or a pharmaceutically acceptable salt thereof.
19. A peptide of claim 18 , wherein
A 3 is Ser or Aib;
A 5 is Ile;
A 7 is Leu or Cha;
A 8 is Met, Nva, Leu, Val, Ile, or Nle;
A 11 is Leu or Cha;
A 15 is Leu or Cha;
A 16 is Asn or Aib;
A 18 is Met, Aib, or Nle;
A 21 is Val;
A 27 is Lys, Aib, Leu, hArg, or Cha;
A 31 is Val, Nle, or Cha;
A 32 is His;
A 33 is Asn;
A 34 is Phe, Tyr, Amp, or Aib;
R 1 is H;
R 2 is H; and
R 3 is NH 2 ;
or a pharmaceutically acceptable salt thereof.
20. A peptide of claim 19 , wherein at least one of A 7 and A 11 is Cha and at least one of A 16 , A 19 , and A 34 is Aib; or a pharmaceutically acceptable salt thereof.
21. A peptide of claim 19 , wherein at least one of A 24 , A 28 , and A 31 is Cha and at least one of A 16 and A 17 is Aib; or a pharmaceutically acceptable salt thereof.
22. A peptide of formula (III):
wherein
A 1 is Ser or Dap;
A 3 is Ser, Thr, or Aib;
A 5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH 3 ;
A 7 is Leu, Ile, Nle, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is H, OH, a halogen, or CH 3 ;
A 8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A 11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 12 is Gly or Aib;
A 15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 16 is Ser, Asn, Ala, or Aib;
A 17 is Ser, Thr, or Aib;
A 18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A 19 is Glu or Aib;
A 21 is Val, Cha, or Met;
A 23 is Trp or Cha;
A 24 is Leu or Cha;
A 27 is Lys, Aib, Leu, hArg, Gln, or Cha
A 28 is Leu or Cha;
A 30 is Asp or Lys;
A 31 is Val, Nle, Cha, or deleted;
A 32 is His or deleted;
A 33 is Asn or deleted;
A 34 is Phe, Tyr, Amp, Aib, or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl, or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxy-phenylalkyl, or C 1-120 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy, or NH'Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H, or CONH 2 ; or a pharmaceutically acceptable salt thereof;
provided that at least one of A 1 is Dap; A 7 is β-Nal, Trp, Pal, Phe, or p-X-Phe; A 15 is β-Nal, Trp, Pal, Phe, or p-X-Phe; A 27 is hArg; or A 31 is Nle;
provided that if A 12 is Gly, then at least one of A 5 is Leu, Nle, β-Nal, Trp, Phe or p-X-Phe; A 11 is Pal or p-X-Phe; or A 15 is Nle, Ile, β-Nal, Trp, Pal, Phe or p-X-Phe;
provided that if A 12 is Aib, then at least one of A 1 is Ser; A 5 is Leu, Nle, β-Nal, Trp, Phe or p-X-Phe; A 11 is Pal or p-X-Phe; or A 15 is Nle, Ile, β-Nal, Trp, Pal, Phe or p-X-Phe;
and also provided that said peptide of formula (III) is not [hArg 27 ]hPTH(1-34)NH 2 .
23. A peptide of claim 22 , wherein
A 1 is Ser or Dap;
A 3 is Ser or Aib;
A 8 is Met, Nva, Leu, Val, Ile, or Nle;
A 16 is Asn or Aib;
A 18 is Met, Aib, or Nle;
A 21 is Val;
A 27 is Lys, Aib, Leu, hArg, or Cha;
A 31 is Val, Nle, or Cha;
A 32 is His;
A 33 is Asn;
A 34 is Phe, Tyr, Amp, or Aib;
R 1 is H;
R 2 is H; and
R 3 is NH 2 ;
or a pharmaceutically acceptable salt thereof.
24. A peptide of the formula: [Nle 31 ]±hPTH±(1-34)NH 2 ; or a pharmaceutically acceptable salt thereof.
25. A peptide of formula (IV):
wherein
A 1 is Ala, Ser, or Dap;
A 3 is Ser or Aib;
A 5 is His, Ile, or Cha;
A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 8 is Leu, Met, or Cha;
A 10 is Asp or Asn;
A 11 is Lys, Leu, Cha, Phe or β-Nal;
A 12 is Gly or Aib;
A 14 is Ser or His;
A 15 is Ile, or Cha;
A 16 is Gln or Aib;
A 17 is Asp or Aib;
A 18 is Leu, Aib, or Cha;
A 19 is Arg or Aib;
A 22 is Phe, Glu, Aib, or Cha;
A 23 is Phe, Leu, Lys, or Cha;
A 24 is Leu, Lys or Cha;
A 25 is His, Aib, or Glu;
A 26 is His, Aib, or Lys;
A 27 is Leu, Lys, or Cha;
A 28 is Ile, Leu, Lys or Cha;
A 29 is Ala, Glu or Aib;
A 30 is Glu, Cha, Aib or Lys;
A 31 is Ile, Leu, Cha, Lys or deleted;
A 32 is His or deleted;
A 33 is Thr or deleted;
A 34 is Ala, Aib or deleted;
each or R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-20 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H, or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 15 , A 18 , A 22 , A 23 , A 24 , A 27 , A 28 , A 30 , or A 31 is Cha, or at least one of A 3 , A 12 , A 16 , A 17 , A 18 , A 19 , A 22 , A 25 , A 26 , A 29 , A 30 , or A 34 is Aib; or a pharmaceutically acceptable salt thereof;
provided that if A 12 is Gly, then at least one of A 1 is Ser; A 5 is Ile; A 8 is Met; A 10 is Asn; A 11 is Leu; A 14 is His; A 22 is Aib; A 23 is Leu or Lys; A 24 is Lys; A 25 is Aib or Glu; A 27 is Lys; A 28 is Leu or Lys; A 29 is Glu or Aib; A 30 is Cha or Aib; A 31 is Leu or Lys; or A 34 is Aib and
provided that said peptide is not [Glu22,25, Leu23,28,31, Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 .
26. A peptide of claim 25 , wherein A 22 is Phe or Cha; A 23 is Phe or Cha; A 25 is His; A 26 is His; A 27 is Leu or Cha; A 28 is Ile or Cha; A 29 is Ala; A 30 is Glu or Lys; A 31 is Ile or Cha; A 32 is His; and A 33 is Thr; or a pharmaceutically acceptable salt thereof.
27. A peptide of claim 26 , wherein at least one of A 7 and A 11 is Cha; or a pharmaceutically acceptable salt thereof.
28. A peptide of claim 26 , wherein at least one of A 16 or A 19 is Aib; or a pharmaceutically acceptable salt thereof.
29. A peptide of claim 25 wherein A 22 is Glu, Aib, or Cha; A 23 is Leu, Lys, or Cha; A 25 is Aib or Glu; A 26 is Aib or Lys; A 28 is Leu, Lys, or Cha; A 29 is Glu or Aib; A 30 is Cha, Aib, or Lys; A 31 is Leu, Cha, or Lys; A 32 is His; A 33 is Thr; and A 34 is Ala; or a pharmaceutically acceptable salt thereof.
30. A peptide of claim 29 , wherein at least one of A 7 and A 11 is Cha; or a pharmaceutically acceptable salt thereof.
31. A peptide of claim 29 , wherein at least one of A 16 or A 19 is Aib; or a pharmaceutically acceptable salt thereof.
32. A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula:
wherein
A 1 is Ser, Ala or Dap;
A 3 is Ser, Thr or Aib;
A 5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 7 is Leu, Nle, Tie, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 8 is Met, Nva, Leu, Val, tie, Cha, Acc or Nle;
A 11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 12 is Gly, Acc or Aib;
A 15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Acc, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 16 is Ser, Asn, Ala or Aib;
A 17 is Ser, Thr or Aib;
A 18 is Met, Nva, Leu, Val, Ile, Nle, Acc, Cha or Aib;
A 19 is Glu or Aib;
A 21 is Val, Acc, Cha or Met;
A 23 is Trp, Acc or Cha;
A 24 is Leu, Acc or Cha;
A 27 is Lys, Aib, Leu, hArg, Gln, Acc or Cha;
A 28 is Leu, Acc or Cha;
A 29 is Gln, Acc or Aib;
A 30 is Asp or Lys;
A 31 is Val, Leu, Nle, Acc, Cha, or deleted;
A 32 is His or deleted;
A 33 is Asn or deleted;
A 34 is Phe, Tyr, Amp, Aib, or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxy-phenylalkyl or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 12 , A 15 , A 18 , A 21 , A 23 , A 24 , A 27 , A 28 , A 29 and A 31 is Acc; or a pharmaceutically acceptable salt thereof.
33. The method according to claim 32 , further comprising administering to said patient a bisphosphonate or calcitonin.
34. A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula:
wherein
A 1 is Ser, Ala, or Dap;
A 3 is Ser, Thr, or Aib;
A 5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen or CH 3 ;
A 7 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A 11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 12 is Gly or Aib;
A 15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 16 is Ser, Asn, Ala or Aib;
A 17 is Ser, Thr or Aib;
A 18 is Met, Nva, Leu, Val, Ile, Nle, Cha or Aib;
A 19 is Glu or Aib;
A 21 is Val, Cha or Met;
A 23 is Trp or Cha;
A 24 is Leu or Cha;
A 27 is Lys, Aib, Leu, hArg, Gln or Cha;
A 28 is Leu or Cha;
A 30 is Asp or Lys;
A 31 is Val, Nle, Cha or deleted;
A 32 is His or deleted;
A 33 is Asn or deleted;
A 34 is Phe, Tyr, Amp, Aib or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxy-phenylalkyl or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 15 , A 18 , A 21 , A 23 , A 24 , A 27 , A 28 , and A 31 is Cha or at least one of A 3 , A 12 , A 16 , A 17 , A 18 , A 19 , and A 34 is Aib; or a pharmaceutically acceptable salt thereof; and
provided that the peptide is not [Aib 12 , Tyr 34 ]hPTH(1-34)NH 2 or [Cha 8 ]hPTH(1-34)NH 2 .
35. The method according to claim 34 , further comprising administering to said patient a bisphosphonate or calcitonin.
36. A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula:
wherein
A 1 is Ser or Dap;
A 3 is Ser, Thr, or Aib;
A 5 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH 3 ;
A 7 is Leu, Ile, Nle, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is H, OH, a halogen or CH 3 ;
A 8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A 11 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 12 is Gly or Aib;
A 15 is Leu, Nle, Ile, Cha, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 16 is Ser, Asn, Ala or Aib;
A 17 is Ser, Thr or Aib;
A 18 is Met, Nva, Leu, Val, Ile, Nle, Cha or Aib;
A 19 is Glu or Aib;
A 21 is Val, Cha or Met;
A 23 is Trp or Cha;
A 24 is Leu or Cha;
A 27 is Lys, Aib, Leu, hArg, Gln or Cha;
A 28 is Leu or Cha;
A 30 is Asp or Lys;
A 31 is Val, Nle, Cha or deleted;
A 32 is His or deleted;
A 33 is Asn or deleted;
A 34 is Phe, Tyr, Amp, Aib or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxy-phenylalkyl, or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 1 is Dap; A 7 is β-Nal, Trp, Pal, Phe, or p-X-Phe; A 15 is β-Nal, Trp, Pal, Phe, or p-X-Phe; A 27 is hArg; or A 31 is Nle or a pharmaceutically acceptable salt thereof; and
provided that said peptide is not [hArg 27 ]hPTH(1-34)NH 2 .
37. The method according to claim 34 , further comprising administering to said patient a bisphosphonate or calcitonin.
38. A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula:
wherein
A 1 is Ala, Ser or Dap;
A 3 is Ser or Aib;
A 5 is His, Ile, or Cha;
A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 8 is Leu, Met or Cha;
A 10 is Asp or Asn;
A 11 is Lys, Leu, Cha, Phe or β-Nal;
A 12 is Gly or Aib;
A 14 is Ser or His;
A 15 is Ile or Cha;
A 16 is Gln or Aib;
A 17 is Asp or Aib;
A 18 is Leu, Aib or Cha;
A 19 is Arg or Aib;
A 22 is Phe, Glu, Aib or Cha;
A 23 is Phe, Leu, Lys or Cha;
A 24 is Leu, Lys or Cha;
A 25 is His, Aib or Glu;
A 26 is His, Aib or Lys;
A 27 is Leu, Lys or Cha;
A 28 is Ile, Leu, Lys or Cha;
A 29 is Ala, Glu or Aib;
A 30 is Glu, Cha, Aib or Lys;
A 31 is Ile, Leu, Cha, Lys or deleted;
A 32 is His or deleted;
A 33 is Thr or deleted;
A 34 is Ala, Aib or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 15 , A 18 , A 22 , A 23 , A 24 , A 27 , A 28 , A 30 , or A 31 is Cha; or at least one of A 3 , A 12 , A 16 , A 17 , A 18 , A 19 , A 22 , A 25 , A 26 , A 29 , A 30 or A 34 is Aib; or a pharmaceutically acceptable salt thereof; and
provided that said peptide is not [Glu22,25, Leu23,28,31, Aib 29 , Lys 26,30 ]hPTHrP(1-34)NH 2 .
39. The method according to claim 38 , further comprising administering to said patient a bisphosphonate or calcitonin.
40. A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula:
wherein
A 1 is Ala, Ser or Dap;
A 3 is Ser or Aib;
A 5 is His, Ile, or Cha;
A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen or CH 3 ;
A 8 is Leu, Met or Cha;
A 10 is Asp or Asn;
A 11 is Lys, Leu, Cha, Phe or β-Nal;
A 12 is Gly or Aib;
A 14 is Ser or His;
A 15 is Ile or Cha;
A 16 is Gln or Aib;
A 17 is Asp or Aib;
A 18 is Leu, Aib or Cha;
A 19 is Arg or Aib;
A 22 is Phe, Glu, Aib, Acc or Cha;
A 23 is Phe, Leu, Lys, Acc or Cha;
A 24 is Leu, Lys, Acc or Cha;
A 25 is His, Aib or Glu;
A 26 is His, Aib or Lys;
A 27 is Leu, Lys, Acc or Cha;
A 28 is Ile, Leu, Lys, Acc or Cha;
A 29 is Ala, Glu or Aib;
A 30 is Glu, Cha, Aib, Acc or Lys;
A 31 is Ile, Leu, Cha, Lys, Acc or deleted;
A 32 is His or deleted;
A 33 is Thr or deleted;
A 34 is Ala or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-2 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2, C 1-12 alkoxy or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 23 , A 24 , A 27 , A 28 or A 31 is Lys or a pharmaceutically acceptable salt thereof.
41. The method according to claim 40 , further comprising administering to said patient a bisphosphonate or calcitonin.
42. A pharmaceutical composition comprising the peptide of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
43. A pharmaceutical composition comprising the peptide of claim 42 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin, and a pharmaceutically acceptable carrier or diluent.
44. A pharmaceutical composition comprising the peptide of claim 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
45. A pharmaceutical composition comprising the peptide of claim 44 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin, and a pharmaceutically acceptable carrier or diluent.
46. A pharmaceutical composition comprising the peptide of claim 22 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
47. A pharmaceutical composition comprising the peptide of claim 46 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin, and a pharmaceutically acceptable carrier or diluent.
48. A pharmaceutical composition comprising the peptide of claim 25 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or diluent.
49. A pharmaceutical composition comprising the peptide of claim 48 or a pharmaceutically acceptable salt thereof, a bisphosphonate or calcitonin, and a pharmaceutically acceptable carrier or diluent.
50. A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a peptide of the formula (VI):
wherein
A 1 is Ala, Ser, or Dap;
A 3 is Ser or Aib;
A 5 is His, Ile, Acc, or Cha;
A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 8 is Leu, Met, Acc, or Cha;
A 10 is Asp or Asn;
A 11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;
A 12 is Gly, Acc, or Aib;
A 14 is Ser or His;
A 15 is Ile, Acc, or Cha;
A 16 is Gln or Aib;
A 17 is Asp or Aib;
A 18 is Leu, Aib, Acc, or Cha;
A 19 is Arg or Aib;
A 22 is Phe, Glu, Aib, Acc, or Cha;
A 23 is Phe, Leu, Lys, Acc, or Cha;
A 24 is Leu, Lys, Acc, or Cha;
A 25 is His, Lys, Aib, Acc, or Glu;
A 26 is His, Aib, Acc, or Lys;
A 27 is Leu, Lys, Acc, or Cha;
A 28 is Ile, Leu, Lys, Acc, or Cha;
A 29 is Ala, Glu, Acc, or Aib;
A 30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;
A 31 is Ile, Leu, Cha, Lys, Acc, or deleted;
A 32 is His or deleted;
A 33 is Thr or deleted;
A 34 is Ala or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkyl C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy, or NH-Y-CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 12 , A 15 , A 18 , A 22 , A 23 , A 24 , A 25 , A 26 , A 27 , A 28 , A 29 , A 30 , or A 31 is Acc; or a pharmaceutically acceptable salt thereof.
51. A method of treating osteoporosis in a patient in need thereof, which comprises administering to said patient a combination of a bisphosphonate or calcitonin and a peptide of the formula (VI):
wherein
A 1 is Ala, Ser, or Dap;
A 3 is Ser or Aib;
As is His, Ile, Acc, or Cha;
A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 8 is Leu, Met, Acc, or Cha;
A 10 is Asp or Asn;
A 11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;
A 12 is Gly, Acc, or Aib;
A 14 is Ser or His;
A 15 is Ile, Acc, or Cha;
A 16 is Gln or Aib;
A 17 is Asp or Aib;
A 18 is Leu, Aib, Acc, or Cha;
A 19 is Arg or Aib;
A 22 is Phe, Glu, Aib, Acc, or Cha;
A 23 is Phe, Leu, Lys, Acc, or Cha;
A 24 is Leu, Lys, Acc, or Cha;
A 25 is His, Lys, Aib, Acc, or Glu;
A 26 is His, Aib, Acc, or Lys;
A 27 is Leu, Lys, Acc, or Cha;
A 28 is Ile, Leu, Lys, Acc, or Cha;
A 29 is Ala, Glu, Acc, or Aib;
A 30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;
A 31 is Ile, Leu, Cha, Lys, Acc, or deleted;
A 32 is His or deleted;
A 33 is Thr or deleted;
A 34 is Ala or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkyl C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 12 , A 15 , A 18 , A 22 , A 23 , A 24 , A 25 , A 26 , A 27 , A 28 , A 29 , A 30 , or A 31 is Acc; or a pharmaceutically acceptable salt thereof.
52. A pharmaceutical composition comprising a bisphosphonate or calcitonin, a pharmaceutically acceptable carrier or diluent, and a peptide of the following formula (VI):
wherein
A 1 is Ala, Ser, or Dap;
A 3 is Ser or Aib;
A 5 is His, Ile, Acc, or Cha;
A 7 is Leu, Cha, Nle, β-Nal, Trp, Pal, Acc, Phe, or p-X-Phe in which X is OH, a halogen, or CH 3 ;
A 8 is Leu, Met, Acc, or Cha;
A 10 is Asp or Asn;
A 11 is Lys, Leu, Cha, Acc, Phe, or β-Nal;
A 12 is Gly, Acc, or Aib;
A 14 is Ser or His;
A 15 is Ile, Acc, or Cha;
A 16 is Gln or Aib;
A 17 is Asp or Aib;
A 18 is Leu, Aib, Acc, or Cha;
A 19 is Arg or Aib;
A 22 is Phe, Glu, Aib, Acc, or Cha;
A 23 is Phe, Leu, Lys, Acc, or Cha;
A 24 is Leu, Lys, Acc, or Cha;
A 25 is His, Lys, Aib, Acc, or Glu;
A 26 is His, Aib, Acc, or Lys;
A 27 is Leu, Lys, Acc, or Cha;
A 28 is Ile, Leu, Lys, Acc, or Cha;
A 29 is Ala, Glu, Acc, or Aib;
A 30 is Glu, Leu, Nle, Cha, Aib, Acc, or Lys;
A 31 is Ile, Leu, Cha, Lys, Acc, or deleted;
A 32 is His or deleted;
A 33 is Thr or deleted;
A 34 is Ala or deleted;
each of R 1 and R 2 is, independently, H, C 1-12 alkyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; or one and only one of R 1 and R 2 is COE 1 in which E 1 is C 1-12 alkyl, C 2-12 alkyl, C 2-12 alkenyl, C 7-20 phenylalkyl, C 11-20 naphthylalkyl, C 1-12 hydroxyalkyl, C 2-12 hydroxyalkenyl, C 7-20 hydroxyphenylalkyl, or C 11-20 hydroxynaphthylalkyl; and
R 3 is OH, NH 2 , C 1-12 alkoxy, or NH—Y—CH 2 -Z in which Y is a C 1-12 hydrocarbon moiety and Z is H, OH, CO 2 H or CONH 2 ;
provided that at least one of A 5 , A 7 , A 8 , A 11 , A 12 , A 15 , A 18 , A 22 , A 23 , A 24 , A 25 , A 26 , A 27 , A 28 , A 29 , A 30 , or A 31 is Acc; or a pharmaceutically acceptable salt thereof.