US2021163536A1PendingUtilityA1
Melanocortin receptor ligands modified with hydantoin
Est. expiryMay 25, 2027(~0.9 yrs left)· nominal 20-yr term from priority
A61P 15/10C07K 14/68A61P 37/06A61P 25/24A61P 31/04A61P 11/06A61P 25/32A61P 13/12A61K 38/00A61P 11/00A61P 37/08A61P 15/00A61P 3/04C07K 7/56A61P 43/00A61P 37/02C07K 7/06A61P 31/18A61P 1/04A61P 37/00A61P 9/00A61P 3/00A61P 19/00A61P 17/02A61P 35/00A61P 1/00A61P 17/06A61P 25/00A61P 19/02A61P 17/00A61P 25/22A61P 9/10A61P 25/04A61P 3/10A61P 29/00
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Claims
Abstract
The present invention relates to peptide ligands of the melanocortin receptors, in particular the melancortin-4 receptor, and as such, are useful in the treatment of disorders responsive to the activation of this receptor, such as obesity, diabetes mellitus and sexual dysfunction.
Claims
exact text as granted — not AI-modified1 . A compound of formula
wherein
X is selected from the group consisting of —CH 2 —S—S—CH 2 —, —C(CH 3 ) 2 —S—S—CH 2 —, —CH 2 —S—S—C(CH 3 ) 2 —, —C(CH 3 ) 2 —S—S—C(CH 3 ) 2 —, —(CH 2 ) 2 —S—S—CH 2 —, —CH 2 —S—S—(CH 2 ) 2 —, —(CH 2 ) 2 —S—S—(CH 2 ) 2 —, —C(CH 3 ) 2 —S—S—(CH 2 ) 2 —, —(CH 2 ) 2 —S—S—C(CH 3 ) 2 , —(CH 2 ) t —C(O)—NR 8 —(CH 2 ) r — and —(CH 2 ) r — NR 8 —C(O)—(CH 2 ) t —;
R 1 and R 2 each is, independently for each occurrence thereof, H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl;
R 3 is —OH or —NH 2 ;
R 4 and R 5 each is, independently for each occurrence thereof, H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl;
X 1 is
A 1 is His, 2-Pal, 3-Pal, 4-Pal, Taz, 2-Thi, 3-Thi, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or deleted;
A 2 is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X 4 , X 2 , X 3 , X 4 , X 5 )Phe;
A 3 is Arg, h Arg, Dab, Dap, Lys or Orn;
A 4 is Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or Trp;
R 6 and R 7 each is, independently for each occurrence thereof, H, (C 1 -C 10 )alkyl, (C 1 -C 10 )heteroalkyl, aryl(C 1 -C 5 )alkyl, substituted (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )heteroalkyl or substituted aryl(C 1 -C 5 )alkyl or R 6 and R 7 may be joined together form a cyclic moiety;
R 8 is H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl;
r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and
t is, independently for each occurrence thereof, 1 or 2; or
a pharmaceutically acceptable salt thereof.
2 . A compound according claim 1 wherein the compound is
cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:1)
cyclo[Hydantoin(C(O)-(hCys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:2)
cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:1)
cyclo[Hydantoin(C(O)-(hCys-D-Ala))-His-D-2-Nal-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:2)
cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:3)
cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH 2 ; (SEQ ID NO:4)
cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH 2 ; (SEQ ID NO:4)
cyclo[Hydantoin(C(O)-(Asp-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH 2 ; (SEQ ID NO:4)
cyclo[Hydantoin(C(O)-(Asp-His))-D-2-Nal-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:5)
cyclo[Hydantoin(C(O)-(Asp-His))-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:5)
cyclo[Hydantoin(C(O)-(Asp-A3c))-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:6)
cyclo[Hydantoin(C(O)-(Asp-A5c))-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:7)
cyclo[Hydantoin(C(O)-(Asp-A6c))-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:8)
cyclo[Hydantoin(C(O)-(Asp-A3c))-D-2-Nal-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:6)
cyclo[Hydantoin(C(O)-(Asp-A5c))-D-2-Nal-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:7)
cyclo[Hydantoin(C(O)-(Asp-A6c))-D-2-Nal-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:8)
cyclo[Hydantoin(C(O)-(Asp-Aic))-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:9)
cyclo[Hydantoin(C(O)-(Asp-Apc))-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:10)
cyclo[Hydantoin(C(O)-(Asp-Aic))-D-2-Nal-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:9)
cyclo[Hydantoin(C(O)-(Asp-Apc))-D-2-Nal-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:10)
cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:68)
cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Orn]-NH 2 ; (SEQ ID NO:11)
cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dab]-NH 2 ; (SEQ ID NO:11)
cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH 2 ; (SEQ ID NO:11)
cyclo[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Dap]-NH 2 ; (SEQ ID NO:12) or
cyclo[Hydantoin(C(O)-(Glu-His))-D-Phe-Arg-Trp-Lys]-NH 2 ; (SEQ ID NO:61)
or a pharmaceutically acceptable salt thereof.
3 . A compound of formula (II)
wherein
X 1 is
X 2 is
A 1 is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen;
A 2 is an L- or D-amino acid;
A 3 is His, 2-Pal, 3-Pal, 4-Pal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe, Taz, 2-Thi or 3-Thi;
A 4 is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X 4 , X 2 , X 3 , X 4 , X 5 )Phe;
A 5 is Arg, hArg, Dab, Dap, Lys or Orn;
A 6 is Bal, 1-Nal, 2-Nal, (X 1 , X 2 , X 3 , X 4 , X 5 )Phe or Trp;
A 7 is Asp, Cys, D-Cys, Dab, Dap, Glu, Lys, Orn, Pen or D-Pen;
R 1 is H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl;
R 2 and R 3 each is, independently, H, (C 1 -C 10 )alkyl, (C 1 -C 10 )heteroalkyl, aryl(C 1 -C 5 )alkyl, substituted (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )heteroalkyl or substituted aryl(C 1 -C 5 )alkyl or R 2 and R 3 may be joined together form a cyclic moiety;
R 4 is CO 2 H or C(O)NH 2 ;
R 5 and R 6 each is, independently, H, (C 1 -C 10 )alkyl, (C 1 -C 10 )heteroalkyl, aryl(C 1 -C 5 )alkyl, substituted (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )heteroalkyl or substituted aryl(C 1 -C 5 )alkyl or R 5 and R 6 may be joined together form a cyclic moiety;
R 7 and R 8 each is, independently, H, (C 1 -C 10 )alkyl, (C 1 -C 10 )heteroalkyl, aryl(C 1 -C 5 )alkyl, substituted (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )heteroalkyl or substituted aryl(C 1 -C 5 )alkyl; or R 7 and R 8 may be joined together form a cyclic moiety;
R 9 is H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl; and
n is, independently for each occurrence thereof, 1, 2, 3, 4, 5, 6 or 7; or
a pharmaceutically acceptable salt thereof.
4 . A compound according to claim 3 wherein said compound is:
Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO: 13)
Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:14)
Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:15)
Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:16)
Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:17)
Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; (SEQ ID NO:18)
Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Pen)-NH 2 ; (SEQ ID NO:19)
Hydantoin(C(O)-(Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:20)
Hydantoin(C(O)-(D-Ala-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:21)
Hydantoin(C(O)-(Aib-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:22)
Hydantoin(C(O)-(Val-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:23)
Hydantoin(C(O)-(Ile-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:24)
Hydantoin(C(O)-(Leu-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:25)
Hydantoin(C(O)-(Gly-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:15)
Hydantoin(C(O)-(Nle-Gly))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:14)
Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:26)
Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:27)
Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:28)
Hydantoin(C(O)-(D-Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:27)
Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:28
Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:29)
Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:30)
Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:31)
Hydantoin(C(O)-(A6c-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:32)
Hydantoin(C(O)-(Gly-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:33)
Hydantoin(C(O)-(Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:34)
Hydantoin(C(O)-(D-Ala-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:35)
Hydantoin(C(O)-(Val-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:36)
Hydantoin(C(O)-(Leu-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:37)
Hydantoin(C(O)-(Cha-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:38)
Hydantoin(C(O)-(Aib-Nle))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:39)
Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:40)
Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-Glu-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:40)
Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:41)
Hydantoin(C(O)-(Gly-Arg))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:41)
Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:42)
Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:42)
Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:43)
Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-D-Ala-His-D-2-Nal-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:43) or
Hydantoin (C(O)-(Nle-Ala))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:44) or
a pharmaceutically acceptable salt thereof.
5 . A compound of formula (III)
wherein
X is selected from the group consisting of —CH 2 —S—S—CH 2 —, —C(CH 3 ) 2 —S—S—CH 2 —, —CH 2 —S—S—C(CH 3 ) 2 —, —C(CH 3 ) 2 —S—S—C(CH 3 ) 2 —, —(CH 2 ) 2 —S—S—CH 2 —, —CH 2 —S—S—(CH 2 ) 2 , —(CH 2 ) 2 —S—S—(CH 2 ) 2 —, —C(CH 3 ) 2 —S—S—(CH 2 ) 2 —, —(CH 2 ) 2 —S—S—C(CH 3 ) 2 —, —(CH 2 ) t —C(O)—NR 8 —(CH 2 ) r — and —(CH 2 ) r — NR 8 —C(O)—(CH 2 ) t —;
R 1 and R 5 each is, independently, H, (C 1 -C 10 )alkyl or substituted (C 1 -C 10 )alkyl;
R 2 and R 3 each is, independently, H, (C 1 -C 10 )alkyl, (C 1 -C 10 )heteroalkyl, aryl(C 1 -C 5 )alkyl, substituted (C 1 -C 10 )alkyl, substituted (C 1 -C 10 )heteroalkyl or substituted aryl(C 1 -C 5 )alkyl or R 2 and R 3 may be joined together to form a ring;
R 4 is —OH or —NH 2 ;
R 6 and R 7 each is, independently, H, (C 1 -C 10 )alkyl or substituted (C 1 —C 10 )alkyl;
A 1 is an L- or D-amino acid or deleted;
A 2 is His, 2-Pal, 3-Pal, 4-Pal, (X 4 ,X 2 ,X 3 ,X 4 ,X 5 )Phe, Taz, 2-Thi or 3-Thi;
A 3 is D-Bal, D-1-Nal, D-2-Nal, D-Phe or D-(X 1 ,X 2 ,X 3 ,X 4 ,X 5 )Phe;
A 4 is Arg, hArg, Dab, Dap, Lys or Orn;
A 5 is Bal, 1-Nal, 2-Nal, (X 4 ,X 2 ,X 3 ,X 4 ,X 5 )Phe or Trp;
r is, independently for each occurrence thereof, 1, 2, 3, 4 or 5; and
t is, independently for each occurrence thereof, 1 or 2; or
a pharmaceutically acceptable salt thereof.
6 . A compound according to claim 5 wherein said compound is:
cyclo[Hydantoin(C(O)-(Nle-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:46)
cyclo[Hydantoin(C(O)-(Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:45)
cyclo[Hydantoin(C(O)-(D-Ala-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:47)
cyclo[Hydantoin(C(O)-(Aib-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:48)
cyclo[Hydantoin(C(O)-(Val-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:49)
cyclo[Hydantoin(C(O)-(Abu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:50)
cyclo[Hydantoin(C(O)-(Leu-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:51)
cyclo[Hydantoin(C(O)-(Ile-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:52)
cyclo[Hydantoin(C(O)-(Cha-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:53)
cyclo[Hydantoin(C(O)-(A6c-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:54)
cyclo[Hydantoin(C(O)-(Phe-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:55)
cyclo[Hydantoin(C(O)-(Gly-Cys))-D-Ala-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:56) or
cyclo[Hydantoin(C(O)-(Gly-Cys))-Glu-His-D-Phe-Arg-Trp-Cys]-NH 2 ; (SEQ ID NO:57) or
a pharmaceutically acceptable salt thereof.
7 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6 and a pharmaceutically acceptable carrier or diluent; or a pharmaceutically acceptable salt thereof.
8 . A pharmaceutical composition according to claim 7 , wherein said compound is a selective melanocortin-4 receptor agonist; or a pharmaceutically acceptable salt thereof.
9 . A pharmaceutical composition according to claim 8 , 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; or a pharmaceutically acceptable salt thereof.
10 . A pharmaceutical composition according to claim 9 , 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; or a pharmaceutically acceptable salt thereof.
11 . A pharmaceutical composition according to claim 9 , 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; or a pharmaceutically acceptable salt thereof.
12 . A pharmaceutical composition according to claim 9 , 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; or a pharmaceutically acceptable salt thereof.
13 . A pharmaceutical composition according to claim 9 , 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; or a pharmaceutically acceptable salt thereof.
14 . 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 6 , or a pharmaceutically acceptable salt thereof.
15 . A method according to claim 14 , wherein said compound is a selective melanocortin-4 receptor agonist.
16 . A method according to claim 15 , wherein said compound is a selective melanocortin-4 receptor agonist with a functional activity characterized by an EC so 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.
17 . A method according to claim 16 , 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.
18 . A method of treating a disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 14 , wherein said disease or condition is selected from the group consisting of:
general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock; rheumatoid arthritis, gouty arthritis and multiple sclerosis; a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders and Prader-Willi Syndrome; a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly; skin cancer and cancer cachexia; endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females; 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; hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia; acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma; enhanced immune tolerance; allergies; psoriasis, skin pigmentation depletion, acne and keloid formation; anxiety, depression, memory dysfunction and neuropathic pain; and renal cachexia and natriuresis.
19 . A method according to claim 18 , wherein obesity is treated.
20 . A method according to claim 18 , wherein a feeding disorder is treated.
21 . A method of decreasing appetite according to claim 18 .
22 . A method according to claim 21 , wherein cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH 2 , (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof is administered.
23 . A method according to claim 21 , wherein-cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH 2 , (SEQ ID NO:11) or a pharmaceutically acceptable salt thereof is administered.
24 . A method of decreasing body weight according to claim 18
25 . A method according to claim 24 , wherein cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH 2 , (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof is administered.
26 . A method according to claim 24 , wherein cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH 2 , (SEQ ID NO:11) or a pharmaceutically acceptable salt thereof is administered.
27 . A method of decreasing appetite and body weight according to claim 18 .
28 . A method according to claim 27 , wherein cyclo[Hydantoin(C(O)-(Cys-D-Ala))-His-D-Phe-Arg-Trp-Cys]-NH 2 , (SEQ ID NO:1) or a pharmaceutically acceptable salt thereof is administered.
29 . A method according to claim 27 , wherein cyclo[Hydantoin(C(O)-(Glu-D-Ala))-His-D-Phe-Arg-Trp-Dap]-NH 2 , (SEQ ID NO:11) or a pharmaceutically acceptable salt thereof is administered.
30 . A method according to claim 18 , wherein anorexia is treated.
31 . A method according to claim 18 , wherein bulimia is treated.
32 . A method according to claim 18 , wherein AIDS wasting or wasting in frail elderly is treated.
33 . A method according to claim 18 , wherein cachexia or cancer cachexia is treated.
34 . 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, nerve growth, bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 14 .
35 . 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 14 .
36 . The use of a therapeutically effective amount of a melanocortin-4 receptor agonist or antagonist according to any one of claims 1 to 6 , 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 and septic shock;
rheumatoid arthritis, gouty arthritis and multiple sclerosis;
a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders and Prader-Willi Syndrome;
a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly;
skin cancer and cancer cachexia;
endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females;
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;
hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia;
acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma;
enhanced immune tolerance;
allergies;
psoriasis, skin pigmentation depletion, acne and keloid formation;
anxiety, depression, memory dysfunction and neuropathic pain; and
renal cachexia and natriuresis.
37 . The use of the medicament according to claim 36 to decrease appetite wherein said medicament comprises Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:42) or a pharmaceutically acceptable salt thereof.
38 . The use of the medicament according to claim 36 to decrease appetite wherein said medicament comprises Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:13) or a pharmaceutically acceptable salt thereof.
39 . The use of the medicament according to claim 36 to decrease body weight wherein said medicament comprises Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:42) or a pharmaceutically acceptable salt thereof.
40 . The use of the medicament according to claim 36 to decrease body weight wherein said medicament comprises Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:13) or a pharmaceutically acceptable salt thereof.
41 . The use of the medicament according to claim 36 to decrease appetite and decrease body weight wherein said medicament comprises Hydantoin(C(O)-(Gly-D-Arg))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:42) or a pharmaceutically acceptable salt thereof.
42 . The use of the medicament according to claim 36 to decrease appetite and decrease body weight wherein said medicament comprises Hydantoin(C(O)-(Arg-Gly))-cyclo(Cys-Glu-His-D-Phe-Arg-Trp-Cys)-NH 2 ; (SEQ ID NO:13) or a pharmaceutically acceptable salt thereof.
43 . The use of a therapeutically effective amount of a melanocortin-4 receptor agonist or antagonist according to any one of claims 1 to 6 , 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.
44 . The use of a therapeutically effective amount of a melanocortin-4 receptor agonist or antagonist according to any one of claims 1 to 6 , or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament useful to inhibit alcohol consumption, reduce alcohol consumption, treat alcoholism, or treat alcohol abuse.
45 . A compound of the formula:
or a pharmaceutically acceptable salt thereof.
46 . A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 45 and a pharmaceutically acceptable carrier or diluent; or a pharmaceutically acceptable salt thereof.
47 . 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 45 , or a pharmaceutically acceptable salt thereof.
48 . A method of treating a disease or medical condition by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 45 , wherein said disease or condition is selected from the group consisting of
an acute or chronic inflammatory disease or medical condition, general inflammation, inflammatory bowel disease, brain inflammation, sepsis and septic shock; an autoimmune disease or medical condition, rheumatoid arthritis, gouty arthritis and multiple sclerosis; a metabolic disease or medical condition accompanied by weight gain, obesity, feeding disorders and Prader-Willi Syndrome; a metabolic disease or medical condition accompanied by weight loss, anorexia, bulimia, AIDS wasting, cachexia, cancer cachexia and wasting in frail elderly; a neoplastic disease or medical condition, skin cancer and cancer cachexia; a reproductive or sexual medical condition, endometriosis, uterine bleeding, sexual dysfunction, erectile dysfunction and decreased sexual response in females; a disease or medical condition resulting from treatment or insult to an organism, 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; a cardiovascular disease or medical condition, hemorrhagic shock, cardiogenic shock, hypovolemic shock, cardiovascular disorders and cardiac cachexia; a pulmonary disease or medical condition, acute respiratory distress syndrome, pulmonary fibrosis, chronic obstructive pulmonary disease and asthma; enhanced immune tolerance; allergies; a dermatological disease or medical condition, psoriasis, skin pigmentation depletion, acne and keloid formation; a behavioral or central nervous system or neuronal disease or medical condition, anxiety, depression, memory dysfunction and neuropathic pain; and a renal disease or medical condition, renal cachexia and natriuresis.
49 . 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, nerve growth, bone metabolism, bone formation and bone development by eliciting an agonist or antagonist effect from a melanocortin receptor according to claim 45 .
50 . 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 45 .Cited by (0)
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