US2016368962A1PendingUtilityA1
Melanocortin Receptor Ligands
Est. expiryJul 8, 2025(expired)· nominal 20-yr term from priority
A61P 37/02A61P 9/12A61P 9/00A61P 37/06A61P 3/08A61P 9/10A61P 5/24A61P 43/00A61P 7/04A61P 9/02A61P 5/00A61P 37/08A61P 3/10A61P 7/00A61P 3/06A61P 35/00A61P 37/04A61P 7/08A61P 25/22A61P 25/24A61P 25/18A61P 25/28A61P 3/00A61P 29/00A61P 25/04A61P 27/02A61P 25/00A61P 25/32A61P 31/04A61P 3/04A61P 25/26A61P 25/02A61P 31/00A61P 3/02A61P 17/00A61P 17/06A61P 15/00A61P 13/12A61P 15/10A61P 1/04A61P 15/06A61P 19/06A61P 11/00A61P 17/10A61P 15/02A61P 11/06A61P 19/08A61P 15/08A61P 19/02A61P 1/00A61P 17/02A61P 1/14A61P 11/08C07K 14/665C07K 7/06A61K 38/00C07K 7/08C07K 2/00
64
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Claims
Abstract
The present invention is directed to compounds according to formula, (R 2 R 3 )-A 1 - c (A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1 , and pharmaceutically-acceptable salts thereof that act as ligands for one or more of the melanocortin receptors, to methods of using such compounds to treat mammals and to pharmaceutical compositions comprising said compounds.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A compound according to formula (I):
(R 2 R 3 )-A 1 - c (A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-A 10 -R 1
wherein:
A 1 is Acc, HN—(CH 2 ) m —C(O), L- or D-amino acid or deleted;
A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu;
A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-amino acid or deleted;
A 4 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi or (X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;
A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal, D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, L-Phe or D-(Et)Tyr;
A 6 is Arg, hArg, Dab, Dap, Lys, Orn or HN—CH((CH 2 ) n —N(R 4 R 5 ))—C(O);
A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip, D-Trp, D-1-Nal, D-2-Nal, D-Bal or D-Bip;
A 8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha, HN—(CH 2 ) s —C(O) or deleted;
A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Dab, Dap, Orn or Lys;
A 10 is Acc, HN—(CH 2 ) t —C(O), L- or D-amino acid or deleted;
R 1 is —OH or —NH 2 ;
R 2 and R 3 is, independently for each occurrence, H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 1 -C 30 )acyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 1 -C 30 )acyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 -C 30 )alkynyl, substituted aryl(C 1 -C 30 )alkyl or substituted aryl(C 1 -C 30 )acyl;
R 4 and R 5 is, independently for each occurrence, H, (C 1 -C 40 )alkyl, (C 1 -C 40 )heteroalkyl, (C 1 -C 40 )acyl, (C 2 -C 40 )alkenyl, (C 2 -C 40 )alkynyl, aryl(C 1 -C 40 )alkyl, aryl(C 1 -C 40 )acyl, substituted (C 1 -C 40 )alkyl, substituted (C 1 -C 4 )heteroalkyl, substituted (C 1 -C 40 ) acyl, substituted (C 2 -C 40 )alkenyl, substituted (C 2 -C 40 )alkynyl, substituted aryl(C 1 -C 40 )alkyl, substituted aryl(C 1 -C 40 )acyl, (C 1 -C 40 )alkylsulfonyl or —C(NH)—NH 2 ;
m is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;
n is, independently for each occurrence, 1, 2, 3, 4 or 5;
s is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7;
t is, independently for each occurrence, 1, 2, 3, 4, 5, 6 or 7; and
X 1 , X 2 , X 3 , X 4 , and X 5 each is, independently for each occurrence, H, F, Cl, Br, I, (C 1-10 )alkyl, substituted (C 1-10 )alkyl, (C 2-10 )alkenyl, substituted (C 2-10 )alkenyl, (C 2-10 )alkynyl, substituted (C 2-10 )alkynyl, aryl, substituted aryl, OH, NH 2 , NO 2 , or CN;
provided that
(I). when R 4 is (C 1 -C 40 )acyl, aryl(C 1 -C 40 )acyl, substituted (C 1 -C 40 )acyl, substituted aryl(C 1 -C 40 )acyl, (C 1 -C 40 )alkylsulfonyl or —C(NH)—NH 2 , then R 5 is H, (C 1 -C 40 )alkyl, (C 1 -C 40 )heteroalkyl, (C 2 -C 40 )alkenyl, (C 2 -C 40 )alkynyl, aryl(C 1 -C 40 )alkyl, substituted (C 1 -C 40 )alkyl, substituted (C 1 -C 40 )heteroalkyl, substituted (C 2 -C 40 )alkenyl, substituted (C 2 -C 40 )alkynyl or substituted aryl(C 1 -C 40 )alkyl;
(II). when R 2 is (C 1 -C 30 )acyl, aryl(C 1 -C 30 )acyl, substituted (C 1 -C 30 )acyl or substituted aryl(C 1 -C 30 )acyl, then R 3 is H, (C 1 -C 30 )alkyl, (C 1 -C 30 )heteroalkyl, (C 2 -C 30 )alkenyl, (C 2 -C 30 )alkynyl, aryl(C 1 -C 30 )alkyl, substituted (C 1 -C 30 )alkyl, substituted (C 1 -C 30 )heteroalkyl, substituted (C 2 -C 30 )alkenyl, substituted (C 2 -C 30 )alkynyl or substituted aryl(C 1 -C 30 )alkyl;
(III). either A 3 or A 8 or both must be present in said compound;
(IV). when A 2 is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen, then A 9 is Cys, D-Cys, hCys, D-hCys, Pen or D-Pen;
(V). when A 2 is Asp or Glu, then A 9 is Dab, Dap, Orn or Lys;
(VI). when A 8 is Ala or Gly, then A 1 is not Nle; and
(VII). when A 1 is deleted, then R 2 and R 3 cannot both be H;
or a pharmaceutically acceptable salt thereof.
2 . A compound according to claim 1 , wherein:
A 1 is A6c, Gaba, Nle, Met, Phe, D-Phe, D-2-Nal, hPhe, Chg, D-Chg, Cha, hCha, hPro, hLeu, Nip, β-hMet or Oic; A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A 3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib or deleted; A 4 is His; A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal or D-(Et)Tyr; A 6 is Arg or hArg; A 7 is Trp, Bip, D-Trp, 1-Nal or 2-Nal; A 8 is A6c, Ala, β-Ala, Gaba, Apn or Ahx; A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen or Lys; and A 10 is Thr or deleted;
or a pharmaceutically acceptable salt thereof.
3 . A compound according to claim 2 , wherein:
R 2 and R 3 is, independently for each occurrence, H, acyl, n-propanoyl or n-butanoyl;
or a pharmaceutically acceptable salt thereof.
4 . A compound according claim 1 , wherein:
A 1 is Acc, Arg, D-Arg, Cha, D-Cha, hCha, Chg, D-Chg, Gaba, Ile, Leu, hLeu, β-hMet, 2-Nal, D-2-Nal, Nip, Nle, Oic, Phe, D-Phe, hPhe, hPro, Val or deleted; A 2 is Cys, D-Cys, Pen or Asp; A 3 is Gly, Ala, β-Ala, Gaba, Aib, D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or deleted; A 4 is His or 3-Pal; A 5 is D-Phe, D-2-Nal or D-(Et)Tyr; A 6 is Arg or hArg; A 7 is Trp, 1-Nal, 2-Nal, Bal, Bip or D-Trp; A 8 is Gly, D-Ala, Acc, Ala, β-Ala, Gaba, Apn, Ahx, Aha or deleted; A 9 is Cys, D-Cys, Pen or Lys; and A 10 is Thr or deleted; provided that either A 3 or A 8 is deleted, but not both;
or a pharmaceutically acceptable salt thereof.
5 . A compound according to claim 4 , wherein said compound is:
SEQ ID NO: 1
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH 2 ;
SEQ ID NO: 1
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH 2 ;
SEQ ID NO: 2
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH 2 ;
SEQ ID NO: 3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH 2 ;
SEQ ID NO: 3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-
NH 2 ;
SEQ ID NO: 3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH 2 ;
SEQ ID NO: 2
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ;
SEQ ID NO: 4
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH 2 ;
SEQ ID NO: 5
Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 6
Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 6
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 6
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 7
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 7
Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 7
Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 7
Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 7
Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 8
Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 8
Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 8
Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 8
Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 8
Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 8
Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 9
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 9
Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 9
Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 9
Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 9
Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 10
Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 10
Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 10
Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 10
Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 10
Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ;
SEQ ID NO: 11
Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 12
n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-
Lys)-NH 2 ;
SEQ ID NO: 11
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 13
Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 13
Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 13
Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 13
Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 13
Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH 2 ;
SEQ ID NO: 14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH 2 ;
SEQ ID NO: 14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH 2 ;
SEQ ID NO: 14
Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH 2 ;
SEQ ID NO: 15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH 2 ;
SEQ ID NO: 15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH 2 ;
SEQ ID NO: 15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH 2 ;
SEQ ID NO: 15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH 2 ;
SEQ ID NO: 16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH 2 ;
SEQ ID NO: 16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH 2 ;
SEQ ID NO: 17
n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-
Cys)-NH 2 ;
SEQ ID NO: 17
n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-
Cys)-NH 2 ;
SEQ ID NO: 18
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH 2 ;
SEQ ID NO: 18
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH 2 ;
SEQ ID NO: 18
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH 2 ;
SEQ ID NO: 61
Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 19
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH 2 ;
SEQ ID NO: 20
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH 2 ;
SEQ ID NO: 21
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 22
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 22
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 23
D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-
NH 2 ;
SEQ ID NO: 24
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-
Cys)-Thr-NH 2 ;
SEQ ID NO: 25
D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-
Cys)-Thr-NH 2 ;
SEQ ID NO: 24
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-
Cys)-Thr-NH 2 ;
SEQ ID NO: 26
D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-
Cys)-Thr-NH 2 ;
SEQ ID NO: 26
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-
Cys)-Thr-NH 2 ;
SEQ ID NO: 27
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ;
SEQ ID NO: 28
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH 2 ;
SEQ ID NO: 28
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH 2 ;
SEQ ID NO: 29
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 31
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 32
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 32
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 33
Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 34
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 34
Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 35
Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 36
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;
SEQ ID NO: 37
Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 38
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 38
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH 2 ;
SEQ ID NO: 39
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 39
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH 2 ;
SEQ ID NO: 40
Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 40
Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 41
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH;
SEQ ID NO: 42
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH;
SEQ ID NO: 43
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH;
SEQ ID NO: 43
D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH;
SEQ ID NO: 43
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH;
SEQ ID NO: 42
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH;
SEQ ID NO: 41
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH;
SEQ ID NO: 44
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;
SEQ ID NO: 44
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;
SEQ ID NO: 29
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;
SEQ ID NO: 44
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;
SEQ ID NO: 44
Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;
SEQ ID NO: 44
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;
SEQ ID NO: 44
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;
SEQ ID NO: 44
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH;
SEQ ID NO: 45
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH;
SEQ ID NO: 45
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH;
SEQ ID NO: 45
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH;
SEQ ID NO: 45
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH;
SEQ ID NO: 46
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH;
SEQ ID NO: 46
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH;
SEQ ID NO: 46
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH;
SEQ ID NO: 46
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH;
SEQ ID NO: 47
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;
SEQ ID NO: 29
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;
SEQ ID NO: 48
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH;
or
SEQ ID NO: 49
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
6 . A compound according to claim 5 , wherein said compound is:
SEQ ID NO: 7
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 22
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 32
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 29
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;
SEQ ID NO: 29
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;
or
SEQ ID NO: 48
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH;
or a pharmaceutically acceptable salt thereof.
7 . A compound according claim 1 , wherein:
A 1 is Arg, D-Arg, Cha, hCha, Chg, D-Chg, Ile, Leu, 2-Nal, Nle, Phe, D-Phe, hPhe, Val or deleted; A 2 is Cys, Pen or Asp; A 3 is D-Ala, D-Abu, D-Cha, D-Ile, D-Leu, D-Tle, D-Val or deleted; A 4 is His or 3-Pal; A 5 is D-Phe, D-2-Nal or D-(Et)Tyr; A 6 is Arg or hArg; A 7 is Trp, 2-Nal, Bal, Bip or D-Trp; A 8 is Gly, Ala, β-Ala, Gaba, Apn, Ahx or deleted; A 9 is Cys, D-Cys, Pen or Lys; A 10 is Thr or deleted; and R 2 and R 3 is, independently for each occurrence, H or acyl;
or a pharmaceutically acceptable salt thereof.
8 . A compound according to claim 7 , wherein said compound is:
SEQ ID NO: 50
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 51
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 52
Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 52
Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 51
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 53
Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 53
Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 7
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 24
D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-
Thr-NH 2 ;
SEQ ID NO: 27
Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ;
SEQ ID NO: 32
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 34
Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 1
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH 2 ;
SEQ ID NO: 2
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH 2 ;
SEQ ID NO: 3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-
NH 2 ;
SEQ ID NO: 3
D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH 2 ;
SEQ ID NO: 2
Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ;
SEQ ID NO: 4
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH 2 ;
SEQ ID NO: 6
Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 6
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 11
Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 15
Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH 2 ;
SEQ ID NO: 21
Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 22
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 23
D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-
NH 2 ;
SEQ ID NO: 25
D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-
NH 2 ;
SEQ ID NO: 24
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-
Thr-NH 2 ;
SEQ ID NO: 26
D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-
NH 2 ;
SEQ ID NO: 26
D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-
Thr-NH 2 ;
SEQ ID NO: 28
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH 2 ;
SEQ ID NO: 28
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH 2 ;
SEQ ID NO: 29
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 30
Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 31
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 32
Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 33
Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 33
Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 34
Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 35
Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 36
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH;
SEQ ID NO: 37
Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 16
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH 2 ;
SEQ ID NO: 20
Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH 2 ;
SEQ ID NO: 38
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 38
Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH 2 ;
SEQ ID NO: 39
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH 2 ;
SEQ ID NO: 39
Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH 2 ;
SEQ ID NO: 40
Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ;
SEQ ID NO: 40
Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ;
or
SEQ ID NO: 49
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
9 . A compound according to claim 1 , wherein:
A 1 is Arg, D-Arg, hArg or D-hArg;
or a pharmaceutically acceptable salt thereof.
10 . A compound according to claim 9 , wherein
A 2 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen, Asp or Glu; A 3 is Gly, Ala, D-Ala, D-Glu, β-Ala, Gaba, Aib or deleted; A 4 is His; A 5 is D-Phe, D-1-Nal, D-2-Nal, D-Trp, D-Bal or D-(Et)Tyr; A 6 is Arg or hArg; A 7 is Trp, Bip, D-Trp, 1-Nal or 2-Nal; A 8 is A6c, Ala, β-Ala, Gaba, Apn or Ahx; A 9 is Cys, D-Cys, hCys, D-hCys, Pen, D-Pen or Lys; A 10 is Thr or deleted;
or a pharmaceutically acceptable salt thereof.
11 . A compound according to claim 10 , wherein:
R 2 and R 3 is, independently for each occurrence, H, acyl, n-propanoyl or n-butanoyl;
or a pharmaceutically acceptable salt thereof.
12 . A compound according to claim 11 , wherein
A 2 is Cys or Asp; A 3 is D-Ala or deleted; A 4 is His; A 5 is D-Phe or D-2-Nal; A 6 is Arg; A 7 is Trp; A 8 is Ala, Gaba or deleted; A 9 is Cys, Pen or Lys; A 10 is deleted;
or a pharmaceutically acceptable salt thereof.
13 . A compound according to claim 12 , wherein:
R 2 and R 3 is, independently for each occurrence, H or acyl;
or a pharmaceutically acceptable salt thereof.
14 . A compound according to claim 13 , wherein said compound is:
SEQ ID NO: 50
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 50
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 51
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 52
Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 52
Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ;
SEQ ID NO: 51
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
SEQ ID NO: 53
Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ;
SEQ ID NO: 53
Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ;
or
SEQ ID NO: 49
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;
or pharmaceutically acceptable salts thereof.
15 . A compound according to claim 14 , wherein said compound is:
SEQ ID NO: 50
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
SEQ ID NO: 51
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
or
SEQ ID NO: 49
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
16 . A compound according to claim 15 , wherein said compound is:
SEQ ID NO: 50
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
17 . A compound according to claim 15 , wherein said compound is:
SEQ ID NO: 51
Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
18 . A compound according to claim 15 , wherein said compound is:
SEQ ID NO: 49
Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
19 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
20 . A pharmaceutical composition according to claim 19 , wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof.
21 . A pharmaceutical composition according to claim 20 , wherein said compound is a selective melanocortin-4 receptor agonist or a pharmaceutically acceptable salt thereof with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin-1 receptor, the human melanocortin-3 receptor and the human melanocortin-5 receptor.
22 . A pharmaceutical composition according to claim 21 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor.
23 . A pharmaceutical composition according to claim 21 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-3 receptor.
24 . A pharmaceutical composition according to claim 21 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor.
25 . A pharmaceutical composition according to claim 21 , wherein the functional activity of the melanocortin-4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin-4 receptor than for the human melanocortin-5 receptor.
26 . A method of eliciting an agonist or antagonist effect from a melanocortin receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
27 . A method according to claim 26 , wherein said compound is a selective melanocortin 4 receptor agonist.
28 . A method according to claim 27 , wherein said compound is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
29 . A method according to claim 28 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
30 . A method according to claim 28 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
31 . A method according to claim 28 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
32 . A method according to claim 28 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
33 . The method according to claim 26 , wherein said subject is in need of treatment of a disease or condition selected from the group consisting of: general inflammation, inflammatory bowel disease, brain inflammation, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, obesity, feeding disorders, Prader-Willi Syndrome, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, diabetes, diabetalogical related conditions and complications of diabetes, retinopathy, skin cancer, endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, decreased sexual response in females, organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, weight loss due to chemotherapy, radiation therapy, or temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, enhanced immune tolerance, allergies, psoriasis, skin pigmentation depletion, acne, keloid formation, psoriasis, skin pigmentation depletion, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.
34 . A method of decreasing food intake according to claim 26 .
35 . A method of decreasing body weight according to claim 26 .
36 . A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 26 .
37 . A method of decreasing food intake by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 34 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 SEQ ID NO:32, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 SEQ ID NO:51, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 SEQ ID NO:22 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 SEQ ID NO:49, or a pharmaceutically acceptable salt thereof.
38 . A method of decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 35 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 SEQ ID NO:32, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 SEQ ID NO:51, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 SEQ ID NO:22 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 SEQ ID NO:49, or a pharmaceutically acceptable salt thereof.
39 . A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 36 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 SEQ ID NO:32, Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:50, Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 SEQ ID NO:51, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 SEQ ID NO:7, D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 SEQ ID NO:24, Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 SEQ ID NO:22, or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 SEQ ID NO:49, or a pharmaceutically acceptable salt thereof.
40 . A method of modulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 26 .
41 . A method of modulating bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 26 .
42 . A method of inhibiting alcohol consumption, reducing alcohol consumption, treating alcoholism, or treating alcohol abuse by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 26 .
43 . A method of inhibiting alcohol consumption according to claim 42 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
44 . A method of reducing alcohol consumption according to claim 42 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
45 . A method of treating alcoholism according to claim 42 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
46 . A method of treating alcohol abuse according to claim 42 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
47 . A method of inhibiting alcohol consumption according to claim 43 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
48 . A method according to claim 47 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
49 . A method according to claim 47 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
50 . A method according to claim 47 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
51 . A method according to claim 47 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
52 . A compound according to formula II:
(R 2 R 3 )-A 1 - c (A 2 -A 3 -A 4 -A 5 -A 6 -A 7 -A 8 -A 9 )-NH 2
wherein:
A 1 is Nle or deleted;
A 2 is Cys or Asp;
A 3 is Glu or D-Ala;
A 4 is His;
A 5 is D-Phe;
A 6 is Arg;
A 7 is Trp, 2-Nal or Bal;
A 8 is Gly, Ala, D-Ala, β-Ala, Gaba or Apn;
A 9 is Cys or Lys;
each of R 2 and R 3 is independently selected from the group consisting of H or (C 1 -C 6 )acyl;
provided that
(I). when R 2 is (C 1 -C 6 )acyl, then R 3 is H; and
(II). when A 2 is Cys, then A 9 is Cys,
or a pharmaceutically acceptable salt thereof.
53 . A compound according to claim 52 , wherein said compound is:
SEQ ID NO: 54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH 2 ;
SEQ ID NO: 54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-
NH 2 ;
SEQ ID NO: 54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-
NH 2 ;
SEQ ID NO: 54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-
NH 2 ;
SEQ ID NO: 54
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ;
SEQ ID NO: 55
Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ;
SEQ ID NO: 55
Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH 2 ;
SEQ ID NO: 56
Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ;
SEQ ID NO: 56
Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH 2 ;
SEQ ID NO: 57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ;
SEQ ID NO: 57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-
NH 2 ;
SEQ ID NO: 57
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-
NH 2 ;
or
SEQ ID NO: 58
Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH 2 ;
or a pharmaceutically acceptable salt thereof.
54 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 52 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
55 . A pharmaceutical composition according to claim 54 , wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof.
56 . A pharmaceutical composition according to claim 55 , wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof, with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
57 . A pharmaceutical composition according to claim 56 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
58 . A pharmaceutical composition according to claim 56 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
59 . A pharmaceutical composition according to claim 56 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
60 . A pharmaceutical composition according to claim 56 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
61 . A method of eliciting an agonist or antagonist effect from a melanocortin receptor in a subject in need thereof which comprises administering to said subject a therapeutically effective amount of a compound according to claim 52 , or a pharmaceutically acceptable salt thereof.
62 . A method according to claim 61 , wherein said compound is a selective melanocortin 4 receptor agonist.
63 . A method according to claim 62 , wherein said compound is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
64 . A method according to claim 63 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
65 . A method according to claim 63 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
66 . A method according to claim 63 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
67 . A method according to claim 63 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
68 . The method according to claim 61 , wherein said subject is in need of treatment of a disease or condition selected from the group consisting of: general inflammation, inflammatory bowel disease, brain inflammation, sepsis, septic shock, rheumatoid arthritis, gouty arthritis, multiple sclerosis, obesity, feeding disorders, Prader-Willi Syndrome, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, diabetes, diabetalogical related conditions and complications of diabetes, retinopathy, skin cancer, endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction, decreased sexual response in females, organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, weight loss due to chemotherapy, radiation therapy, or temporary or permanent immobilization and dialysis, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders, cardiac cachexia, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, enhanced immune tolerance, allergies, psoriasis, skin pigmentation depletion, acne, keloid formation, psoriasis, skin pigmentation depletion, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.
69 . A method of decreasing food intake according to claim 61 .
70 . A method of decreasing body weight according to claim 61 .
71 . A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 61 .
72 . A method of treating a metabolic disease or medical condition accompanied by weight loss by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 61 , wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
73 . A method of modulating ovarian weight, placental development, prolactin secretion, FSH secretion, intrauterine fetal growth, parturition, spermatogenesis, thyroxin release, aldosterone synthesis and release, body temperature, blood pressure, heart rate, vascular tone, brain blood flow, blood glucose levels, sebum secretion, pheromone secretion, motivation, learning and behavior, pain perception, neuroprotection and nerve growth by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 61 .
74 . A method of modulating bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 61 .
75 . A method of inhibiting alcohol consumption, reducing alcohol consumption, treating alcoholism, or treating alcohol abuse by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 61 .
76 . A method of inhibiting alcohol consumption according to claim 75 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
77 . A method of reducing alcohol consumption according to claim 75 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
78 . A method of treating alcoholism according to claim 75 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
79 . A method of treating alcohol abuse according to claim 75 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
80 . A method of inhibiting alcohol consumption according to claim 76 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist with a functional activity characterized by an EC 50 at least 15-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 1 receptor, the human melanocortin 3 receptor and the human melanocortin 5 receptor.
81 . A method according to claim 80 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
82 . A method according to claim 80 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
83 . A method according to claim 80 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
84 . A method according to claim 80 , wherein the functional activity of the melanocortin 4 receptor agonist is characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
85 . A method of treating diabetes, diabetalogical related conditions and complications of diabetes, said method comprising administering a compound of either claim 1 or 52 to a subject in need.
86 . The method of claim 85 , wherein said complication of diabetes is retinopathy.Cited by (0)
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