Cyclic peptide-based NPR-B agonists
Disclosed are cyclic, peptide-based novel compounds having NPR-B agonistic activity. Preferred compounds are cyclic peptides containing conventional or non-conventional L- or D-amino acid residues connected to one another via peptide bonds. In some embodiments, provided herein are a cyclic peptide compound with a ring size that is significantly reduced as compared to known NPR-B agonists, such as CNP.
1. A compound of the Formula:
wherein
Y 1 is selected from the group consisting of —S—, —O—, —S—S—, —CO—NH—, and —NH—CO—;
j and o are, independently, 1 or 2;
B is H, C 1-10 alkyl; alkanoyl; sulfanoyl; alkylcycloalkyl; or aralkyl;
Z is H, —CH 2 —OH, and —C(═O)—X 11 , wherein X 11 is selected from the group consisting of OH, —NR 11 R 13 , and —OR 14 ;
wherein R 11 and R 13 are, independently, selected from the group consisting of H and C 1-6 alkyl; and
R 14 is selected from the group consisting of H, C 1-10 alkyl, and alkylcycloalkyl.
2. The compound of claim 1 , wherein Y 1 is —S—S—.
3. The compound of claim 1 , wherein j is 1 and o is 1.
4. The compound of claim 1 , wherein B is a moiety of Formula (XV):
wherein
Y 2 is selected from the group consisting of —CH 2 —, —C(═O)—, and —SO 2 —;
Y 3 is absent or, if present, is selected from the group consisting of H, —NH 2 , and —NHC(═O)—CH 3 ; and
R 12 is selected from the group consisting of C 1-8 alkyl, alkylcycloalkyl, aryl, aralkyl, and alkylsulfide.
5. The compound of claim 1 , wherein
B is selected from the group consisting of Met, Nle, Hgl, met, nle, hgl, a N-acetylated derivative of any of the preceding amino acids, Hex, and Occ;
Y 1 is —S—S—;
j is 1;
o is 1; and
Z is —C(═O)—NR 11 R 13 , wherein R 11 and R 13 are, independently, selected from the group consisting of H and C 1-6 alkyl.
6. The compound of claim 1 , wherein the compound is
Hex-cyclo(Cys-pro-Phe-Gly-Leu-Pro-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:89).
7. A compound of Formula XII:
Xaa 1 -cyclo(Cys-Xaa 2 -Xaa 3 -Gly-Leu-Xaa 4 -Xaa 5 -Asp-Arg-Ile-Ser-Xaa 6 )-Z (XII)
wherein
Xaa 1 is selected from the group consisting of Met, Hex, iPrEtCO, iPrPrCO, Occ, PhEtCO, and PhPrCO, provided that when Xaa 1 is iPrEtCO, iPrPrCO, Occ, PhEtCO, or PhPrCO then Xaa 2 is ala, Xaa 3 is Phe, Xaa 4 is Lys, Xaa 5 is Leu, Xaa 6 is Cys, and Z is NH 2 ;
Xaa 2 is selected from the group consisting of ala, aze, thz, pip and pro, provided that when Xaa 2 is aze, thz, pip or pro then Xaa 1 is Hex;
Xaa 3 is selected from the group consisting of Phe, Mcf and Mmf, provided that when Xaa 3 is Mcf or Mmf then Xaa 1 is Hex;
Xaa 4 is selected from the group consisting of Pro, Lys, Hpa and Hpr, provided that when Xaa 4 is Hpa or Hpr then Xaa 1 is Hex;
Xaa 5 is selected from the group consisting of Leu, Ile, Nle, and Npg, provided that when Xaa 5 is Nle or Npg then Xaa 1 is Hex;
Xaa 6 is selected from the group consisting of Cys and Cea, provided that when Xaa 6 is Cea then Xaa 1 is Met or Hex and Z is H; and
Z is selected from the group consisting of NH 2 and H.
8. The compound of claim 7 , wherein the compound is selected from the group consisting of:
H-Met-cyclo(Cys-ala-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:49); H-Met-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:53); H-Met-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cea) (SEQ ID NO:61); iPrEtCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:64); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:65); iPrPrCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:67); Occ-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:68); PhEtCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:70); PhPrCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:72); Hex-cyclo(Cys-ala-Mcf-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:77); Hex-cyclo(Cys-aze-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:79); Hex-cyclo(Cys-thz-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:80); Hex-cyclo(Cys-pip-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:81); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Nle-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:83); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Hpa-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:85); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Hpr-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:86); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:87); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Pro-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:88); Hex-cyclo(Cys-pro-Phe-Gly-Leu-Pro-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:89); Hex-cyclo(Cys-pro-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:90); Hex-cyclo(Cys-pro-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:91); Hex-cyclo(Cys-pro-Phe-Gly-Leu-Lys-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:92); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:93); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Npg-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:95); Hex-cyclo(Cys-ala-Mmf-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO: 104); and Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cea) (SEQ ID NO: 120).
9. A compound of Formula XIV:
Xaa 1 -cyclo(Cys-Xaa 2 -Xaa 3 -Gly-Xaa 4 -Lys-Leu-Asp-Xaa 5 -Xaa 6 -Ser-Cys)-Z (XIV)
Wherein
Xaa 1 is selected from the group consisting of Met, Hex, Nle and H, provided that when Xaa 1 is Nle then Xaa 2 is His, Xaa 3 is Phe, Xaa 4 is Leu, Xaa 5 is Arg, Xaa 6 is Ile, and Z is NH 2 , and when Xaa 1 is H, then Xaa 2 is ala, Xaa 3 is Phe, Xaa 4 is Leu, Xaa 5 is Arg, Xaa 6 is Ile, and Z is NH 2 ;
Xaa 2 is selected from the group consisting of His, Gab, phe and ala, provided that when Xaa 2 is Gab or phe then Xaa 1 is Met;
Xaa 3 is selected from the group consisting of Phe, Pcf, Pff, and Mtf, provided that when Xaa 3 is Pcf, or Pff then Xaa 1 is Met, and when Xaa 3 is Mtf then Xaa 1 is Hex;
Xaa 4 is selected from the group consisting of Leu and Ala, provided that when Xaa 4 is Ala then Xaa 1 is Met;
Xaa 5 is selected from the group consisting of Arg, Bmr, Aof, and Nar, provided that when Xaa 5 is Bmr, Aof or Nar then Xaa 1 is Hex, Xaa 2 is ala, Xaa 3 is Phe, Xaa 4 is Leu, Xaa 6 is Ile and Z is NH 2 ;
Xaa 6 is selected from the group consisting of Ile, Atp and Att, provided that when Xaa 6 is Atp or Att then Xaa 1 is Hex, Xaa 2 is ala, Xaa 3 is Phe, Xaa 4 is Leu, Xaa 5 is Arg and Z is NH 2 ; and
Z is selected from the group consisting of NH 2 , Trp-Arg-NH 2 , His-Arg-NH 2 , OH, and Tyr-Ser-NH 2 , provided that when Z is anything other than NH 2 then Xaa 1 is Met, Xaa 2 is His, Xaa 3 is Phe, Xaa 4 is Leu, Xaa 5 is Arg, and Xaa 6 is Ile.
10. The compound of claim 9 , wherein the compound is selected from the group consisting of:
iPrEtCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:64); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:65); iPrPrCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:67); Occ-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:68); PhEtCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:70); and PhPrCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:72).
11. A compound of the Formula:
wherein
Y 1 is selected from the group consisting of —S—, —O—, —S—S—, —CO—NH—, and —NH—CO—; and
j and o are, independently, 1 or 2;
B is H, C 1-10 alkyl; alkanoyl; sulfanoyl; alkylcycloalkyl; or aralkyl; and
Z is H, —CH 2 —OH, and —C(═O)—X 11 , wherein X 11 is selected from the group consisting of OH, —NR 11 R 13 , or —OR 14 ;
wherein R 11 and R 13 are, independently, selected from the group consisting of H and C 1-6 alkyl; and
R 14 is selected from the group consisting of H, C 1-10 alkyl, and alkylcycloalkyl.
12. The compound of claim 11 , wherein Y 1 is —S—S—.
13. The compound of claim 11 , wherein j is 1 and o is 1.
14. The compound of claim 11 , wherein the compound is selected from the group consisting of:
H-Met-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cea) (SEQ ID NO:61); iPrEtCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:64); Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:65); iPrPrCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:67); Occ-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:68); PhEtCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:70); and PhPrCO-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:72).
15. A compound of the Formula:
wherein
Y 1 is selected from the group consisting of —S—, —O—, —S—S—, —CO—NH—, and —NH—CO—; and
j and o are, independently, 1 or 2;
B is H, C 1-10 alkyl; alkanoyl; sulfanoyl; alkylcycloalkyl; or aralkyl; and
Z is H, —CH 2 —OH, and —C(═O)—X 11 , wherein X 11 is selected from the group consisting of OH, —NR 11 R 13 , or —OR 14 ;
wherein R 11 and R 13 are, independently, selected from the group consisting of H and C 1-6 alkyl; and
R 14 is selected from the group consisting of H, C 1-10 alkyl, and alkylcycloalkyl.
16. The compound of claim 15 , wherein Y 1 is —S—S—.
17. The compound of claim 15 , wherein the compound is H-Met-cyclo(Cys-ala-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:49); or Hex-cyclo(Cys-ala-Phe-Gly-Leu-Pro-Leu-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:93).
18. A compound of the Formula:
wherein
Y 1 is selected from the group consisting of —S—, —O—, —S—S—, —CO—NH—, and —NH—CO—; and
j and o are, independently, 1 or 2;
B is H, C 1-10 alkyl; alkanoyl; sulfanoyl; alkylcycloalkyl; or aralkyl; and
Z is H, —CH 2 —OH, and —C(═O)—X 11 , wherein X 11 is selected from the group consisting of OH, —NR 11 R 13 , or —OR 14 ;
wherein R 11 and R 13 are, independently, selected from the group consisting of H and C 1-6 alkyl; and
R 14 is selected from the group consisting of H, C 1-10 alkyl, and alkylcycloalkyl.
19. The compound of claim 18 , wherein Y 1 is —S—S—.
20. The compound of claim 18 , wherein the compound is H-Met-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:53); or Hex-cyclo(Cys-ala-Phe-Gly-Leu-Lys-Ile-Asp-Arg-Ile-Ser-Cys)-NH 2 (SEQ ID NO:87).