Peptide compositions
The present invention relates to polypeptide compounds that are modulators (e.g., agonists and antagonists) of the melanocortin-4 receptor (MC4R) and pharmaceutical compositions comprising same. The compounds described herein are polypeptide of the following structural Formula (I): or a pharmaceutically acceptable salt thereof. Values and preferred values of the variables in structural Formula (I) are described herein.
1. An isolated polypeptide of the following structural Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is —H, or a C1-C6 acyl;
R 2 is —NR 3 R 4 , or —OR 5 wherein R 3 , R 4 , and R 5 are each independently is-H or a C1-C6 alkyl;
A 1 Nle;
A 2 and A 8 is each independently an amino acid residue selected from Cys, hCys, Glu, or Dpr, wherein A 2 and A 8 are pairwise selected so as to be able to form a covalent bond between their respective side chains;
A 3 is an amino acid residue selected from Ala, Tle, Val, Leu, Ile, Cha, Pro, Ser, Thr, Lys, Arg, His, Phe, Gln, Sar, Gly, Asn, Aib, or
A 3 is absent, or
A 3 is residue Y, wherein Y is an amino acid selected from amino acids represented by the following structural formulas
wherein:
R 11 and R 12 , each independently, is H, —CH 3 , phenyl, or benzyl;
R 21 , R 22 , R 23 , and R 24 , each independently is H, —CH 3 , —CF 3 , phenyl, benzyl, F, Cl, Br, I, —OCH 3 , or —OH;
R 31 , R 32 , R 33 , R 34 , R 41 , R 42 , and R 43 , each independently is H, —CH 3 , —CF 3 , phenyl, benzyl, F, Cl, Br, I, —OCH 3 , or —OH;
A 4 is absent or an optionally substituted His;
A 5 is an optionally substituted Phe
A 6 is Arg; and
A 7 is Trp,
wherein any amino acid residue is either in L- or in D-configuration.
2. The polypeptide of claim 1 , wherein A 5 is an optionally substituted D-Phe.
3. A pharmaceutical composition comprising the polypeptide of claim 1 or a pharmaceutically acceptable salt thereof in a pharmaceutically acceptable carrier.
4. The polypeptide of claim 1 , represented by any one of the following structural formulas:
Ac-Nle-cyclo[hCys-Pro-D-Phe-Arg-Trp-Cys]-NH 2 (SEQ ID NO: 21); or
Ac-Nle-cyclo[Dpr-Ala-D-Phe-Arg-Trp-Glu]-NH 2 (SEQ ID NO: 32).
5. The polypeptide of claim 1 , represented by the following structural formula:
Ac-Nle-cyclo[hCys-Pro-D-Phe-Arg-Trp-Cys]-NH 2 (SEQ ID NO: 21).
6. The polypeptide of claim 1 , represented by the following structural formula:
Ac-Nle-cyclo[Dpr-Ala-D-Phe-Arg-Trp-Glu]-NH 2 (SEQ ID NO: 32).