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 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, Ile, Cha, β-Nal, Trp, Acc, 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, 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.
2. The method according to claim 1 , further comprising administering to said patient a bisphosphonate or calcitonin.