Melanocortin receptor-specific heptapeptides
Inventors
Shi, Yi-Qun • Sharma, Shubh D. • Dodd, John H. • Yang, Wei
Assignees
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Publication Number
US-9458201-B2
Publication Date
2016-10-04
Expiration Date
Abstract
Melanocortin receptor-specific cyclic heptapeptides of the formula Z-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Y (II) or a pharmaceutically acceptable salt thereof, where Z, Xaa1, Xaa2, Xaa3, Xaa4, Xaa5, Xaa6, Xaa7 and Y are as defined in the specification, compositions and formulations including the peptides of the foregoing formula, and methods of preventing, ameliorating or treating melanocortin receptor-mediated diseases, indications, conditions and syndromes.
Core Innovation
The invention relates to cyclic heptapeptides of formula (II) or a pharmaceutically acceptable salt thereof, having a defined sequence framework Z-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Y. Z is H or an N-terminal group, Y is a C-terminal group, and Xaa2 and Xaa7 form a lactam-containing cyclic bridge, thereby constraining the cyclic peptide structure.
The peptide framework further defines side-chain functionality requirements across Xaa1 to Xaa6. Xaa1 has a side chain including at least one primary amine, guanidine or urea group; Xaa3 is Pro optionally substituted with defined substituents or an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl; Xaa4 has a side chain including unsubstituted phenyl or naphthyl; Xaa5 is Pro or an amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether; and Xaa6 has a side chain including at least one aryl or heteroaryl with independently defined optional ring substituents.
The disclosed embodiments include cyclic heptapeptides based on Ac-Arg-cyclo(Asp-D-Phe-Arg-Trp-Lys)-NH2 scaffold and related variants, with residue substitutions at the D-amino-acid positions and variation at Xaa2. Examples include Ac-Arg-cyclo(Asp-D-Trp-D-Phe-Arg-Trp-Lys)-NH2, Ac-Arg-cyclo(Asp-D-Thr(Bzl)-D-Phe-Arg-Trp-Lys)-NH2, Ac-Arg-cyclo(Asp-Gln-D-Phe-Arg-Trp-Lys)-OH, and other depicted compound structures with C-terminal amide or hydroxyl forms.
The invention excludes specific cyclic peptide combinations, including cases where Z is Ac and where particular residue groupings and residue identities occur together with Y selected as —OH or —NH2. The claim set also includes compositions and treatment-related coverage associated with the cyclic heptapeptide scaffold.
Claims Coverage
The claim coverage centers on one independent claim for a cyclic heptapeptide of formula (II) or a pharmaceutically acceptable salt thereof, with a lactam-containing cyclic bridge formed by Xaa2 and Xaa7, defined Z and Y positions, side-chain constraints for Xaa1 to Xaa6, and explicit exclusions. The claim set also includes dependent features that narrow Z and Y and add pharmaceutical composition and treatment layers.
Cyclic heptapeptide of formula (II) with lactam-containing cyclic bridge
A cyclic heptapeptide of formula (II) or a pharmaceutically acceptable salt thereof, wherein Z is H or an N-terminal group; Xaa1 has a side chain including at least one primary amine, guanidine or urea group; Xaa2 and Xaa7 are amino acids whose side chains form a lactam-containing cyclic bridge; Xaa3 is Pro optionally substituted with defined substituents or an amino acid with a side chain including at least one primary amine, secondary amine, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, ether, sulfide, or carboxyl; Xaa4 has a side chain including unsubstituted phenyl or naphthyl; Xaa5 is Pro or an amino acid with a side chain including at least one primary amine, secondary amine, guanidine, urea, alkyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl, or ether; Xaa6 has a side chain including at least one aryl or heteroaryl with independently defined optional ring substituents; and Y is a C-terminal group.
Specific Z acyl-group selection for the cyclic heptapeptide
Z is a C1 to C7 acyl group selected from cyclohexanoyl, cyclopentylacetyl, cyclohexylacetyl, or phenylacetyl.
C-terminal group defined with hydroxyl or amide forms
The C-terminal group is either a hydroxyl, an amide, or an amide substituted with one or two specified C1 to C17 hydrocarbon/heterocyclic or unsaturated chains.
Exclusion of specific cyclic peptide combinations
The cyclic heptapeptide excludes cyclic peptides wherein Z is Ac and Xaa1 is Arg, and where Xaa2 and Xaa7 together are Glu...Orn, Orn...Glu, or Asp...Lys, with Xaa3 being Pro or Ser(Bzl), Xaa4 being D-Phe, Xaa5 being Arg, Xaa6 being Trp, and Y being —OH or —NH2.
Pharmaceutical composition including the cyclic peptide
A pharmaceutical composition that includes the cyclic peptide together with a pharmaceutically acceptable carrier.
Method of treating melanocortin receptor-mediated disease or condition
A method of treating a mammal by administering the pharmaceutical composition for a melanocortin receptor-mediated disease or condition.
Overall, the claims are directed to a cyclic heptapeptide scaffold of formula (II) with a lactam-containing cyclic bridge between Xaa2 and Xaa7, defined residue and terminal-group constraints, and explicit exclusions of certain peptide combinations. Dependent coverage narrows Z and Y and adds pharmaceutical composition and melanocortin receptor-mediated treatment coverage.
Stated Advantages
Selectivity favoring MC4-R over MC1-R by at least ~20-fold.
Documented MC4-R agonist functional activity with EC50 values reported in the provided summary content.
Documented in vivo effects in rats including reduced food intake/weight change and penile erection effects for example peptides.
Documented pharmacokinetic half-life reported for an example peptide.
Documented Applications
Treatment of a mammal by administering the pharmaceutical composition for a melanocortin receptor-mediated disease or condition.
Peptide-based pharmaceutical compositions for prophylaxis and/or treatment of melanocortin receptor-mediated diseases/conditions, including MC4-R related disorders involving obesity/feeding and sexual dysfunction.
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