US2018305406A1PendingUtilityA1
Melanocortin Receptor Ligands
Est. expiryJul 8, 2025(expired)· nominal 20-yr term from priority
A61P 3/08A61P 35/00A61P 3/06A61P 9/10A61P 37/02A61P 9/00A61P 43/00A61P 9/02A61P 5/00A61P 37/04A61P 9/12A61P 3/10A61P 5/24A61P 7/08A61P 7/04A61P 7/00A61P 37/08A61P 37/06A61P 25/28A61P 25/22A61P 27/02A61P 25/18A61P 3/04A61P 3/02A61P 25/32A61P 31/04A61P 25/02A61P 31/00A61P 29/00A61P 3/00A61P 25/24A61P 25/04A61P 25/00A61P 25/26A61P 15/00A61P 11/00A61P 1/00A61P 19/08A61P 11/08A61P 15/08A61P 17/10A61P 17/00A61P 19/06A61P 13/12A61P 17/06A61P 11/06A61P 17/02A61P 15/02A61P 1/04A61P 15/10A61P 15/06A61P 19/02A61P 1/14C07K 7/06A61K 38/00C07K 7/08C07K 14/665C07K 2/00
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Claims
Abstract
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 40 )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 4 )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:
Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-A6c-Lys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH 2 ; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH 2 ; Ac-A6c-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-D-2-Nal-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(D-Cys-Gly-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(Cys-Gly-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(D-Cys-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(D-Cys-D-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(D-Cys-β-Ala-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(D-Cys-Gaba-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Nle-c(D-Cys-Aib-His-D-Phe-Arg-Trp-D-Cys)-NH 2 ; Ac-Oic-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Nip-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-hPro-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-hLeu-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-D-Phe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; n-butanoyl-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-β-hMet-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Gaba-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Cha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ; Ac-hCha-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ; Ac-Leu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ; Ac-hLeu-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ; Ac-Phe-c(Asp-His-D-Phe-Arg-D-Trp-Ala-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-D-Ala-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-β-Ala-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Gaba-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Aha-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-D-Trp-Apn-Lys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Apn-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-NH 2 ; n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH 2 ; n-butanoyl-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-1-Nal-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Bal-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-D-Ala-Lys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH 2 ; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D (Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH 2 ; Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH 2 ; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Bala-Lys)-NH 2 ; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH 2 ; Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-OH; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Ala-D-Cys)-Thr-OH; D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-OH; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-OH; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-OH; Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-D-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Gaba-Cys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-Ahx-Cys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-D-Ala-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-1-Nal-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-OH; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-OH; or 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:
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; or 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:
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ; Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-3β-Ala-D-Cys)-Thr-NH 2 ; Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-β-Ala-Lys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Ahx-Cys)-NH 2 ; D-Phe-c(Cys-His-D-Phe-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-D-Cys)-Thr-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Apn-Lys)-NH 2 ; Ac-Cha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-hCha-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-D-Chg-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-hPhe-c(Asp-His-D-Phe-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Nle-c(Cys-His-D-Phe-Arg-D-Trp-β-Ala-Cys)-NH 2 ; Ac-Nle-c(Pen-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; D-Phe-c(Cys-His-D-Phe-hArg-Trp-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-Phe-Arg-Bip-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Trp-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-Phe-hArg-Bip-β-Ala-D-Cys)-Thr-NH 2 ; D-Phe-c(Cys-His-D-(Et)Tyr-hArg-Bip-β-Ala-D-Cys)-Thr-NH 2 ; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Trp-Lys)-NH 2 ; Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Lys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-OH; Ac-Nle-c(Cys-D-Abu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Val-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ile-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Leu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Tle-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Cha-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Pen-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Leu-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Cha-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Ile-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Val-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-2-Nal-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Phe-c(Cys-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-3-Pal-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-OH; Ac-Nle-c(Cys-His-Phe-Arg-D-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-2-Nal-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-2-Nal-Arg-Bal-Cys)-NH 2 ; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-Ala-Lys)-NH 2 ; Ac-Nle-c(Asp-His-D-2-Nal-Arg-Trp-β-Ala-Lys)-NH 2 ; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-His-D-2-Nal-Arg-Trp-Ahx-Cys)-NH 2 ; Ac-hPhe-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ; Ac-Cha-c(Asp-His-D-2-Nal-Arg-Trp-Gaba-Lys)-NH 2 ; or 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:
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; Ac-D-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Arg-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 ; Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; Ac-D-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ; Ac-Arg-c(Asp-His-D-Phe-Arg-Trp-Ala-Lys)-NH 2 ; or 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:
Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; or 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:
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:
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:
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 any one of claims 1 to 18 , 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 pharmaceutical composition according to claim 19 useful for treating an acute or chronic inflammatory disease or medical condition wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
27 . A pharmaceutical composition according to claim 19 useful for treating a disease or medical condition with an autoimmune component wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
28 . A pharmaceutical composition according to claim 19 useful for treating a metabolic disease or medical condition accompanied by weight gain wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
29 . A pharmaceutical composition according to claim 28 , wherein obesity is treated.
30 . A pharmaceutical composition according to claim 28 , wherein a feeding disorder is treated.
31 . A pharmaceutical composition according to claim 19 useful for decreasing food intake.
32 . A pharmaceutical composition according to claim 19 useful for decreasing body weight.
33 . A pharmaceutical composition according to claim 19 useful for decreasing food intake and decreasing body weight.
34 . A pharmaceutical composition according to claim 31 useful for decreasing food intake wherein said compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 , Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
35 . A pharmaceutical composition according to claim 34 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
36 . A pharmaceutical composition according to claim 34 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
37 . A pharmaceutical composition according to claim 34 useful for decreasing food intake wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , or a pharmaceutically acceptable salt thereof.
38 . A pharmaceutical composition according to claim 32 useful for decreasing body weight wherein said compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 , Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
39 . A pharmaceutical composition according to claim 38 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
40 . A pharmaceutical composition according to claim 38 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
41 . A pharmaceutical composition according to claim 38 useful for decreasing food intake wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , or a pharmaceutically acceptable salt thereof.
42 . A pharmaceutical composition according to claim 33 useful for decreasing food intake and decreasing body weight wherein said compound is selected from the group consisting of Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 , Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 and Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
43 . A pharmaceutical composition according to claim 42 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
44 . A pharmaceutical composition according to claim 42 useful for decreasing food intake wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
45 . A pharmaceutical composition according to claim 42 useful for decreasing food intake wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , or a pharmaceutically acceptable salt thereof.
46 . A pharmaceutical composition according to claim 19 useful for treating a metabolic disease or medical condition accompanied by weight loss wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
47 . A pharmaceutical composition according to claim 46 useful for treating anorexia.
48 . A pharmaceutical composition according to claim 46 useful for treating bulimia.
49 . A pharmaceutical composition according to claim 46 useful for treating AIDS wasting or wasting in frail elderly.
50 . A pharmaceutical composition according to claim 46 useful for treating cachexia or cancer cachexia.
51 . A pharmaceutical composition according to claim 19 useful for treating a neoplastic disease or medical condition wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
52 . A pharmaceutical composition according to claim 19 useful for treating a reproductive or sexual medical condition wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
53 . A pharmaceutical composition according to claim 19 useful for treating a disease or medical condition resulting from treatment or insult to an organism wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
54 . A pharmaceutical composition according to claim 19 useful for treating a cardiovascular disease or medical condition wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
55 . A pharmaceutical composition according to claim 19 useful for treating a pulmonary disease or medical condition wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
56 . A pharmaceutical composition according to claim 19 useful for treating a disease or medical condition wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
57 . A pharmaceutical composition according to claim 19 useful for treating a dermatological disease or medical condition wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
58 . A pharmaceutical composition according to claim 19 useful for treating a behavioral or central nervous system or neuronal disease or medical condition wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
59 . A pharmaceutical composition according to claim 19 useful for treating a renal disease or medical condition wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
60 . A pharmaceutical composition according to claim 19 useful for 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.
61 . A pharmaceutical composition according to claim 19 useful for modulating bone metabolism, bone formation and bone development.
62 . A pharmaceutical composition according to claim 19 useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or for treating alcohol abuse.
63 . A pharmaceutical composition according to claim 62 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
64 . A pharmaceutical composition according to claim 62 useful for reducing alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
65 . A pharmaceutical composition according to claim 62 useful for treating alcoholism wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
66 . A pharmaceutical composition according to claim 62 useful for treating alcohol abuse wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
67 . A pharmaceutical composition according to claim 63 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting 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.
68 . A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
69 . A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
70 . A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
71 . A pharmaceutical composition according to claim 67 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
72 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to inhibit alcohol consumption in a subject in need of such treatment.
73 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist of according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to reduce alcohol consumption in a subject in need of such treatment.
74 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcoholism in a subject in need of such treatment.
75 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcohol abuse in a subject in need of such treatment.
76 . 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 any one of claims 1 to 18 , or a pharmaceutically acceptable salt thereof.
77 . A method according to claim 76 , wherein said compound is a selective melanocortin 4 receptor agonist.
78 . A method according to claim 77 , 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.
79 . A method according to claim 78 , 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.
80 . A method according to claim 78 , 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.
81 . A method according to claim 78 , 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.
82 . A method according to claim 78 , 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.
83 . A method of treating an acute or chronic inflammatory disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
84 . A method of treating a disease or medical condition with an autoimmune component by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
85 . A method of treating a metabolic disease or medical condition accompanied by weight gain by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
86 . A method according to claim 85 , wherein obesity is treated.
87 . A method according to claim 85 , wherein a feeding disorder is treated.
88 . A method of decreasing food intake according to claim 76 .
89 . A method of decreasing body weight according to claim 76 .
90 . A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 .
91 . A method of decreasing food intake by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 88 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 , Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
92 . A method according to claim 91 , wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
93 . A method according to claim 91 , wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
94 . A method according to claim 91 , wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , or a pharmaceutically acceptable salt thereof.
95 . A method of decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 89 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 , Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
96 . A method according to claim 95 , wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
97 . A method according to claim 95 , wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
98 . A method according to claim 95 , wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , or a pharmaceutically acceptable salt thereof.
99 . A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 90 wherein said compound is Ac-Nle-c(Cys-His-D-Phe-Arg-Trp-Gaba-Pen)-NH 2 , Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , D-Phe-c(Cys-His-D-(Et)Tyr-Arg-Trp-β-Ala-D-Cys)-Thr-NH 2 , Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , or Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
100 . A method according to claim 99 , wherein said compound is 22493 Ac-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
101 . A method according to claim 99 , wherein said compound is Ac-Arg-c(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 , or a pharmaceutically acceptable salt thereof.
102 . A method according to claim 99 , wherein said compound is Ac-D-Arg-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 , or a pharmaceutically acceptable salt thereof.
103 . 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 76 , wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
104 . A method according to claim 103 , wherein anorexia is treated.
105 . A method according to claim 103 , wherein bulimia is treated.
106 . A method according to claim 103 , wherein AIDS wasting or wasting in frail elderly is treated.
107 . A method according to claim 103 , wherein cachexia or cancer cachexia is treated.
108 . A method of treating a neoplastic disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
109 . A method of treating a reproductive or sexual medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
110 . A method of treating a disease or medical condition resulting from treatment or insult to an organism by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
111 . A method of treating a cardiovascular disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
112 . A method of treating a pulmonary disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
113 . A method of treating a disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
114 . A method of treating a dermatological disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
115 . A method of treating a behavioral or central nervous system or neuronal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
116 . A method of treating a renal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 76 , wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
117 . 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 76 .
118 . 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 76 .
119 . 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 76 .
120 . A method of inhibiting alcohol consumption according to claim 119 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
121 . A method of reducing alcohol consumption according to claim 119 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
122 . A method of treating alcoholism according to claim 119 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
123 . A method of treating alcohol abuse according to claim 119 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
124 . A method of inhibiting alcohol consumption according to claim 120 , 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.
125 . A method according to claim 124 , 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.
126 . A method according to claim 124 , 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.
127 . A method according to claim 124 , 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.
128 . A method according to claim 124 , 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.
129 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 1 - 18 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat 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, a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders, Prader-Willi Syndrome, a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, 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 a medical procedure selected from the group consisting of chemotherapy, radiation therapy, 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, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.
130 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 1 - 18 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to modulate 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, nerve growth, bone metabolism, bone formation and bone development.
131 . 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.
132 . A compound according to claim 131 , wherein said compound is:
Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gly-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-D-Ala-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Apn-Cys)-NH 2 ; Ac-c(Cys-Glu-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ; Ac-c(Cys-Glu-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH 2 ; Ac-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ; Ac-c(Cys-D-Ala-His-D-Phe-Arg-2-Nal-Ala-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Ala-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-β-Ala-Cys)-NH 2 ; Ac-Nle-c(Cys-D-Ala-His-D-Phe-Arg-Trp-Gaba-Cys)-NH 2 ; or Ac-Nle-c(Asp-D-Ala-His-D-Phe-Arg-Bal-Ala-Lys)-NH 2 ; or a pharmaceutically acceptable salt thereof.
133 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or diluent.
134 . A pharmaceutical composition according to claim 133 , wherein said compound is a selective melanocortin 4 receptor agonist, or a pharmaceutically acceptable salt thereof.
135 . A pharmaceutical composition according to claim 134 , 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.
136 . A pharmaceutical composition according to claim 135 , 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.
137 . A pharmaceutical composition according to claim 135 , 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.
138 . A pharmaceutical composition according to claim 135 , 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.
139 . A pharmaceutical composition according to claim 135 , 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.
140 . A pharmaceutical composition according to claim 133 useful for treating an acute or chronic inflammatory disease or medical condition wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
141 . A pharmaceutical composition according to claim 133 useful for treating a disease or medical condition with an autoimmune component wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
142 . A pharmaceutical composition according to claim 133 useful for treating a metabolic disease or medical condition accompanied by weight gain wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
143 . A pharmaceutical composition according to claim 142 , wherein obesity is treated.
144 . A pharmaceutical composition according to claim 142 , wherein a feeding disorder is treated.
145 . A pharmaceutical composition according to claim 133 useful for decreasing food intake.
146 . A pharmaceutical composition according to claim 133 useful for decreasing body weight.
147 . A pharmaceutical composition according to claim 133 useful for decreasing food intake and decreasing body weight.
148 . A pharmaceutical composition according to claim 133 useful for treating a metabolic disease or medical condition accompanied by weight loss wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
149 . A pharmaceutical composition according to claim 148 useful for treating anorexia.
150 . A pharmaceutical composition according to claim 148 useful for treating bulimia.
151 . A pharmaceutical composition according to claim 148 useful for treating AIDS wasting or wasting in frail elderly.
152 . A pharmaceutical composition according to claim 148 useful for treating cachexia or cancer cachexia.
153 . A pharmaceutical composition according to claim 133 useful for treating a neoplastic disease or medical condition wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
154 . A pharmaceutical composition according to claim 133 useful for treating a reproductive or sexual medical condition wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
155 . A pharmaceutical composition according to claim 133 useful for treating a disease or medical condition resulting from treatment or insult to an organism wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
156 . A pharmaceutical composition according to claim 133 useful for treating a cardiovascular disease or medical condition wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
157 . A pharmaceutical composition according to claim 133 useful for treating a pulmonary disease or medical condition wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
158 . A pharmaceutical composition according to claim 133 useful for treating a disease or medical condition wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
159 . A pharmaceutical composition according to claim 133 useful for treating a dermatological disease or medical condition wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
160 . A pharmaceutical composition according to claim 133 useful for treating a behavioral or central nervous system or neuronal disease or medical condition wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
161 . A pharmaceutical composition according to claim 133 useful for treating a renal disease or medical condition wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
162 . A pharmaceutical composition according to claim 133 useful for 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.
163 . A pharmaceutical composition according to claim 133 useful for modulating bone metabolism, bone formation and bone development.
164 . A pharmaceutical composition according to claim 133 useful for inhibiting alcohol consumption, for reducing alcohol consumption, for treating alcoholism, or for treating alcohol abuse.
165 . A pharmaceutical composition according to claim 164 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
166 . A pharmaceutical composition according to claim 164 useful for reducing alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
167 . A pharmaceutical composition according to claim 164 useful for treating alcoholism wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
168 . A pharmaceutical composition according to claim 164 useful for treating alcohol abuse wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
169 . A pharmaceutical composition according to claim 165 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting 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.
170 . A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 17-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
171 . A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 90-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 3 receptor.
172 . A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 200-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
173 . A pharmaceutical composition according to claim 169 useful for inhibiting alcohol consumption wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist exhibiting a function activity characterized by an EC 50 at least 3000-fold more selective for the human melanocortin 4 receptor than for the human melanocortin 5 receptor.
174 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to inhibit alcohol consumption in a subject in need of such treatment.
175 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist of according to any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to reduce alcohol consumption in a subject in need of such treatment.
176 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcoholism in a subject in need of such treatment.
177 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist according to c any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat alcohol abuse in a subject in need of such treatment.
178 . 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 any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof.
179 . A method according to claim 178 , wherein said compound is a selective melanocortin 4 receptor agonist.
180 . A method according to claim 179 , 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.
181 . A method according to claim 180 , 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.
182 . A method according to claim 180 , 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.
183 . A method according to claim 180 , 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.
184 . A method according to claim 180 , 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.
185 . A method of treating an acute or chronic inflammatory disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock.
186 . A method of treating a disease or medical condition with an autoimmune component by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of rheumatoid arthritis, gouty arthritis and multiple sclerosis.
187 . A method of treating a metabolic disease or medical condition accompanied by weight gain by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of obesity, feeding disorders and Prader-Willi Syndrome.
188 . A method according to claim 187 , wherein obesity is treated.
189 . A method according to claim 187 wherein a feeding disorder is treated.
190 . A method of decreasing food intake according to claim 178 .
191 . A method of decreasing body weight according to claim 178 .
192 . A method of decreasing food intake and decreasing body weight by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 .
193 . 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 178 , wherein said disease or condition is selected from the group consisting of anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly.
194 . A method according to claim 193 , wherein anorexia is treated.
195 . A method according to claim 193 , wherein bulimia is treated.
196 . A method according to claim 193 , wherein AIDS wasting or wasting in frail elderly is treated.
197 . A method according to claim 193 , wherein cachexia or cancer cachexia is treated.
198 . A method of treating a neoplastic disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of skin cancer and cancer cachexia.
199 . A method of treating a reproductive or sexual medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females.
200 . A method of treating a disease or medical condition resulting from treatment or insult to an organism by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of organ transplant rejection, ischemia and reperfusion injury, wounding and spinal cord injury, and weight loss due to a medical procedure selected from the group consisting of chemotherapy, radiation therapy, temporary or permanent immobilization and dialysis.
201 . A method of treating a cardiovascular disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia.
202 . A method of treating a pulmonary disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma.
203 . A method of treating a disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of enhanced immune tolerance and allergies.
204 . A method of treating a dermatological disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of psoriasis, skin pigmentation depletion, acne and keloid formation.
205 . A method of treating a behavioral or central nervous system or neuronal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of anxiety, depression, memory dysfunction and neuropathic pain.
206 . A method of treating a renal disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 178 , wherein said disease or condition is selected from the group consisting of renal cachexia and natriuresis.
207 . 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 178 .
208 . 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 178 .
209 . 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 178 .
210 . A method of inhibiting alcohol consumption according to claim 209 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
211 . A method of reducing alcohol consumption according to claim 209 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
212 . A method of treating alcoholism according to claim 209 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
213 . A method of treating alcohol abuse according to claim 209 , wherein said compound of said pharmaceutical composition is a selective melanocortin 4 receptor agonist.
214 . A method of inhibiting alcohol consumption according to claim 210 , 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.
215 . A method according to claim 214 , 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.
216 . A method according to claim 214 , 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.
217 . A method according to claim 214 , 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.
218 . A method according to claim 214 , 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.
219 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to treat 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, a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders, Prader-Willi Syndrome, a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia, wasting in frail elderly, 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 a medical procedure selected from the group consisting of chemotherapy, radiation therapy, 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, anxiety, depression, memory dysfunction, neuropathic pain, renal cachexia and natriuresis.
220 . The use of a therapeutically effective amount of a melanocortin 4 receptor agonist or antagonist according to any one of claims 131 or 132 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to modulate 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, nerve growth, bone metabolism, bone formation and bone development.Cited by (0)
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