Melanocortin-1 receptor-specific linear peptides
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Publication Number
US-9580466-B2
Publication Date
2017-02-28
Expiration Date
Abstract
Melanocortin receptor-specific linear peptides of the formula where R1, R2, R3, R4, R5, R6, R7, R8, R9 and R10 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 linear peptides and pharmaceutically acceptable salts thereof. The peptides are defined by a linear formula (II) having constrained substituent positions, including R1, R2, R6, R8, R10, R11, R12, R19, R20a, R20b, w, and z, with defined classes for amino-acid-derived substituents, an acyl group, and linker ranges. A specific encompassed example is Ac-Nle-Ala-His-D-Phe-Arg-Ala-Trp-NH2 (SEQ ID NO:4).
The linear peptides selectively act at melanocortin receptor (MCR-1 and MCR-4). The structural constraint defines a peptide class intended to achieve MCR-related activity, and comparative assay results are described for linear melanocortin peptide variants, including reported Ki values and MC-1 EC50/% maximal response in a cAMP HBL assay. These comparative data are presented to relate peptide structure to MC-1/MC-4 receptor activity and support structure-activity relationships.
The disclosed therapeutic scope includes diseases and conditions associated with MC1R-mediated or responsive activity, including inflammatory and cytokine-mediated conditions, fibrotic/sclerotic disorders, dermatologic and cosmetic indications, ocular diseases including dry eye and uveitis, ischemia and ischemia-reperfusion injury, circulatory shock, photosensitive viral infections, skin diseases and cancers, therapy-related phototoxicity, and increased melanin production and tanning. The peptides are also described in renal ischemia/reperfusion injury, transplant organ perfusion, targeted imaging, and cytotoxic therapy for melanoma using radionuclides conjugated to peptides.
Claims Coverage
The provided material includes two independent claims: one defining a broad class of linear peptides by formula (II), and one covering a specific linear peptide sequence. Across these independent claims, the inventive features are structural constraints on the linear peptide composition and, for the second independent claim, a particular fixed sequence.
Formula (II) linear peptide and pharmaceutically acceptable salts
A linear peptide of formula (II) or a pharmaceutically acceptable salt thereof, wherein R1 is −R11−R12; R2 is −H or −CH3; R6 is defined by specified (CH2)w substituted and nitrogen/amide-containing linkages; R8 is −H or a C1−C10 linear alkyl, cycloalkyl or alkyl cycloalkyl; R10 is −R11−R19; R11 is independently optionally present and, if present, is 1 to 3 L- or D-isomer amino acids; R12 is a C1 to C7 acyl group; R19 is −OH, −N(R20a)(R20b), −N(R20a)(CH2)w-cycloalkyl, or −O−(CH2)w-cycloalkyl; R20a and R20b are each independently H or a C1 to C4 chain; w is 0 to 5; and z is 1 to 5.
Specific linear peptide sequence Ac-Nle-Ala-His-D-Phe-Arg-Ala-Trp-NH2
A linear peptide consisting of Ac-Nle-Ala-His-D-Phe-Arg-Ala-Trp-NH2 (SEQ ID NO:4).
Overall, the claims coverage centers on a class of formula (II) linear peptides defined by multi-parameter substituent constraints, with a further independent claim directed to a specific fixed linear peptide sequence (SEQ ID NO:4).
Stated Advantages
The comparative assay results show Ki values spanning orders of magnitude and corresponding EC50/efficacy differences across the linear peptide variants.
Documented Applications
Comparative assay results for linear melanocortin peptide variants using reported MC-4 Ki, MC-1 Ki, and MC-1 EC50/% maximal response in a cAMP HBL assay to support structure-activity relationships for MC-1/MC-4 receptor activity.
Therapeutic use for MCR-1-mediated or responsive diseases, with emphasis on inflammatory and cytokine-mediated conditions.
Treatment of fibrotic/sclerotic disorders.
Dermatologic and cosmetic indications, including skin diseases and cancers.
Therapeutic use for photosensitive or photoreactive viral infections, including herpes simplex virus, human papilloma virus, and varicella zoster virus.
Therapeutic use for therapy-related phototoxicity.
Increasing melanin production and tanning.
Therapeutic use for ocular diseases, including dry eye and uveitis.
Therapeutic use for ischemia and ischemia-reperfusion injury, including renal ischemia/reperfusion injury.
Therapeutic use for transplant organ perfusion.
Therapeutic use for circulatory shock, including hemorrhagic, cardiogenic, hypovolemic, vasodilatory, and septic shock.
Targeted imaging and cytotoxic therapy for melanoma using radionuclides conjugated to peptides.
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