Melanocortin-1 receptor-specific linear peptides
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Publication Number
US-10106578-B2
Publication Date
2018-10-23
Expiration Date
Abstract
Melanocortin receptor-specific linear peptides of the formula Z-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Y (VI) or a pharmaceutically acceptable salt thereof, where Z, Y, Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, and Xaa6 are as defined in the specification, compositions and formulations including peptides of the foregoing formula or salts thereof, and pharmaceutical compositions for preventing, ameliorating or treating melanocortin-1 receptor-mediated or responsive diseases, indications, conditions and syndromes.
Core Innovation
The invention relates to isolated linear peptides, including pharmaceutical salts of the peptides, defined by a positional sequence formula Z–Xaa1–Xaa2–Xaa3–Xaa4–Xaa5–Xaa6–Y, in which Z is a C1 to C7 acyl and Y is an amide. The peptide positions are constrained to specific residue types and isomeric forms, including L- or D-variants for selected amino acids and an optional substitution set for one residue position.
In the described peptide definitions, Xaa2 is an L-isomer of Ala, His or Pro, optionally substituted with hydroxyl, halogen, sulfonamide, alkyl, –O-alkyl, aryl, alkyl-aryl, alkyl-O-aryl, alkyl-O-alkyl-aryl, or –O-aryl. Xaa3 is L- or D-Phe with optional substituents from a listed set, Xaa4 is an L-isomer of selected basic or polar residues including Met(O), Orn, Dap, or Dab, and Xaa6 is L- or D-Trp, with additional constraints on Xaa1 and Xaa5.
The invention further includes specific linear peptides selected from a group of named sequences identified by SEQ ID NOs, including N-terminally acetylated forms and C-terminally amidated or hydroxyl-ended variants. Pharmaceutical compositions are also covered by combining the defined linear peptides, or pharmaceutically acceptable salts thereof, with a pharmaceutically acceptable carrier.
Claims Coverage
The document provides two independent claim sets. One independent claim broadly covers an isolated linear peptide defined by a residue-type positional formula, and the other independent claim lists a group of specific linear peptides selected from SEQ ID NOs; together they define the peptide structures and cover related pharmaceutical compositions.
Positional formula-defined isolated linear peptide
An isolated linear peptide, or a pharmaceutically acceptable salt, defined by a sequence formula Z–Xaa1–Xaa2–Xaa3–Xaa4–Xaa5–Xaa6–Y, where Z is a C1 to C7 acyl and Y is an amide, with Xaa1 through Xaa6 constrained to specific residue identities, L- or D-isomer requirements, and an optional substitution set for Xaa2 and Xaa3.
Selected set of specific linear peptides identified by seq id nos
A linear peptide selected from a group consisting of specific SEQ ID NO peptides, including N-terminal acetylated forms and C-terminal amidated or hydroxyl-ended variants, explicitly enumerated in the claim, including variants such as Ac-Nle-Ala-His-D-Phe-Arg-Ala-Trp-NH2 and other listed sequences.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the linear peptide, or a pharmaceutically acceptable salt of it, together with a pharmaceutically acceptable carrier.
Overall, the claims cover peptide structures defined either by constrained positional residue types or by enumerated SEQ ID NO sequences, and extend the coverage to pharmaceutical compositions including pharmaceutically acceptable carrier and salt forms.
Stated Advantages
Provides cAMP HBL activation performance differences among peptide analogs, including variants with lower MC-1 Ki and corresponding cAMP HBL activation.
Reports functional activity using MC-4 Ki and MC-1 Ki and provides EC50 and Emax values for cAMP HBL activation where available.
Documented Applications
Use in evaluation via the cAMP HBL assay, including reporting MC-4 Ki and MC-1 Ki and measuring cAMP HBL activation, EC50 and Emax, for the peptide analogs.
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