Melanocortin receptor-specific peptides
Inventors
Shi, Yi-Qun • Sharma, Shubh D. • Dodd, John H. • Yang, Wei
Assignees
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Publication Number
US-10179804-B2
Publication Date
2019-01-15
Expiration Date
Abstract
Melanocortin receptor-specific cyclic peptides of the formula where R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 and z 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 peptides selected from an enumerated group of specific cyclic peptide sequences. The cyclic peptides share an Ac-Arg-cyclo(...) framework, including cyclo(Asp-X-D-Phe-Arg-Trp-Lys) and related variants, with specified N-terminal and C-terminal forms such as NH2, OH, NH-cyclopropyl, and NH-Et embodiments. The disclosure also includes pharmaceutically acceptable salt forms of the listed cyclic peptides.
Within the enumerated group, the cyclic peptides are defined by combinations of residues including Asp, Glu, His, Lys, Ser, Ala, D-Phe, Cit, Trp, Arg, Orn, Dab, Dap, Hyp, Gln, Asn, Pro(4R-Bzl), Tyr, Leu, Nle, Thr(Bzl), Hyp(Bzl), Val, Aic, Gly, Ile, Met(O2), Sar, hGlu, and other explicitly listed substitutions and modified side-chain forms. The disclosure also includes variants with caps and residue modifications such as cyclohexanoyl, cyclopentylacetyl, cyclohexylacetyl, phenylacetyl, Met(O2), and Phe(2-C(=O)NH2), Phe(3-(C(=O)NH2)), and Phe(4-(C(=O)NH2)).
The patent further defines cyclic peptide formulae with variable substituents and exclusions, including a cyclic heptapeptide scaffold formula with a lactam-containing cyclic bridge via Xaa2/Xaa7. The peptides are described as melanocortin receptor-specific cyclic peptide therapeutics, and the disclosure also includes pharmaceutical compositions and methods of treating melanocortin receptor-mediated diseases or conditions responsive to melanocortin receptor function.
Claims Coverage
The provided material covers two independent claim themes directed to a defined set of cyclic peptide sequences and to treatment uses, with dependent claims to pharmaceutical compositions. The inventive features combine specified cyclic peptide scaffolds, terminal forms and residue substitutions, pharmaceutically acceptable salts, a pharmaceutically acceptable carrier, and administration for melanocortin receptor-mediated disease or conditions responsive to melanocortin receptor function.
Enumerated cyclic peptide scaffold with specified terminal forms
A cyclic peptide selected from the group consisting of the listed Ac-Arg-cyclo(...) cyclic peptide sequences and related variants, including cyclo(Asp-X-D-Phe-Arg-Trp-Lys) forms, with residue substitutions and modified residues explicitly listed in the claim set and terminal forms such as NH2, OH, NH-cyclopropyl, and NH-Et.
Pharmaceutically acceptable salts of the enumerated cyclic peptides
The cyclic peptide of the enumerated group is also claimed as a pharmaceutically acceptable salt of any of the foregoing.
Pharmaceutical composition with a pharmaceutically acceptable carrier
A pharmaceutical composition comprising a cyclic peptide of the claim or a pharmaceutically acceptable salt of the cyclic peptide and a pharmaceutically acceptable carrier.
Method of treating a melanocortin receptor-mediated disease by administering the composition
A method of treating a melanocortin receptor-mediated disease in a human or a non-human mammal comprising administering the pharmaceutical composition.
Method treating a condition responsive to melanocortin receptor function by administering the composition
A method of treating a condition in a human or a non-human mammal responsive to changes in melanocortin receptor function comprising administering the pharmaceutical composition.
Claim coverage is centered on the enumerated cyclic peptide set and its pharmaceutically acceptable salts, with dependent coverage extending to pharmaceutical compositions and administration-based therapeutic use for melanocortin receptor-mediated diseases or conditions responsive to melanocortin receptor function.
Stated Advantages
Higher selectivity at MC4-R than MC1-R, with peptides reported as MC4-R agonists.
Reported in vivo activity outcomes including rat penile erection and rat feeding studies for selected peptides.
Reported circulation half-life of approximately 0.7 h for peptides 154 and 155.
The disclosed melanocortin receptor-specific cyclic peptides are described as intended for treatment, prevention, or amelioration of melanocortin receptor-mediated diseases.
The document states effectiveness over a significant dose range.
The disclosure includes aspects relating to sexual dysfunction and obesity/energy homeostasis.
Documented Applications
Rat penile erection studies using selected peptides in Sprague-Dawley rats.
Rat feeding studies using selected peptides in Sprague-Dawley rats.
Methods of treatment by administering a pharmaceutical composition comprising the cyclic peptide or its pharmaceutically acceptable salt to humans or non-human mammals for melanocortin receptor-mediated diseases or conditions responsive to melanocortin receptor function.
Treatment, prevention, or amelioration of melanocortin receptor-mediated diseases.
Aspects relating to sexual dysfunction and obesity/energy homeostasis.
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