Melanocortin receptor-specific peptide with C-terminal naphthylalanine
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Publication Number
US-10711039-B2
Publication Date
2020-07-14
Expiration Date
Abstract
Melanocortin receptor-specific peptides with a C-terminal naphthylalanine of the formula: where R4, R7, R9, R11, R18, R20, R21a, R21b, R21c and R22 are as defined in the claims, compositions and formulations including the peptides of the foregoing formula or salts thereof, and methods of preventing, ameliorating or treating melanocortin receptor-mediated or responsive diseases, indications, conditions and syndromes.
Core Innovation
The invention provides cyclic peptides of a formula, including all enantiomers, stereoisomers or diastereoisomers, and pharmaceutically acceptable salts of any of the foregoing. The cyclic peptide structure is defined by specific substituent variables including R4, R7, R9, R11, R14, R16, R18, R19a, R19b, R20, R21a, R21b, R21c, R22, and index ranges for w, x, y, and z, with optional substitution patterns for rings and other substituent options.
In particular selections, the cyclic peptide is selected from Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-D-Nal1-NH2 (SEQ ID NO:12), Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Nal2-NH2 (SEQ ID NO:13), Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-D-Nal2-NH2 (SEQ ID NO:14), and Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Nal1-NH2 (SEQ ID NO:33), or pharmaceutically acceptable salts thereof. The provided assay data relate to melanocortin receptor activity for MC-1 and MC-4, including competitive binding and cAMP accumulation results with reported Ki and cAMP HBL EC50/Emax values.
The invention is used in melanocortin receptor settings, including melanocortin receptor-mediated disease and conditions that respond to changes in melanocortin receptor function. It also describes therapeutic application scope for cytokine and/or growth factor responsive cancers, ocular inflammatory diseases, ischemia and ischemia-reperfusion injury, neuroprotection, and circulatory shock.
Claims Coverage
The claim coverage is anchored by broad structural formula-defined cyclic peptides and by specific selected Nal-containing cyclic peptide variants identified by SEQ ID NOs. Across these independent claims, the inventive features center on structural formula-defined cyclic peptides and specific Nal-containing cyclic peptide sequences, including pharmaceutically acceptable salts.
Structural formula-defined cyclic peptide variants
A cyclic peptide of the formula including all enantiomers, stereoisomers or diastereoisomers thereof, or a pharmaceutically acceptable salt of any of the foregoing, wherein R4 is —(CH2)w—R14; R7 is —(CH2)w—R16; R9 is a —(CH2)x— and —(CH2)y— carbonyl or amino linkage arrangement with specified alternatives; R11 is H or a C1 to C7 acyl group; R14, R16, R18, R19a/R19b, R20, R21a/R21b/R21c, and R22 are defined with listed substituent options and optional ring substitution; and w, x, y, z have defined ranges.
Selected Nal-containing cyclic peptide variants
A cyclic peptide selected from the group consisting of Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-D-Nal1-NH2 (SEQ ID NO:12), Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Nal2-NH2 (SEQ ID NO:13), Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-D-Nal2-NH2 (SEQ ID NO:14), and Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-Nal1-NH2 (SEQ ID NO:33), or a pharmaceutically acceptable salt of any of the foregoing.
Overall, the claim coverage is centered on broad structural formula-defined cyclic peptides, including stereoisomers and pharmaceutically acceptable salts, and on specific selected Nal-containing cyclic peptide variants identified by SEQ ID NOs.
Stated Advantages
Selective MCR-1 agonists for preventing, ameliorating, or treating MCR-1 mediated or responsive diseases.
Functional potency and activity can vary among the cyclized peptide sequences, enabling selection and use of specific cyclic peptide forms and salts.
Predominantly very high selectivity for MC-1 activity, with low MC-1 Ki and sub-micromolar to low-micromolar cAMP HBL EC50 values in many variants.
MC-4 Ki values are generally much higher relative to MC-1 Ki, supporting MC-1 selectivity.
Measured maximal responses (Emax) for cAMP HBL are typically near complete activation.
Documented Applications
Bioactivity assay readouts for multiple cyclized peptide variants (SEQ ID NOs 30–53), including MC-4 Ki and MC-1 Ki (average), plus MC-1 EC50 and MC-1 Emax in a cAMP HBL assay, supporting melanocortin receptor agonist/functional activity differences across sequence variants.
Preventing/ameliorating/treating MCR-1 mediated or responsive inflammatory diseases and inflammatory bowel disease (IBD).
Preventing/ameliorating/treating MCR-1 mediated or responsive fibrotic/sclerotic diseases.
Preventing/ameliorating/treating cytokine-mediated diseases.
Preventing/ameliorating/treating dermatologic/cosmetic diseases including acne, atopic dermatitis, psoriasis, and vitiligo.
Preventing/ameliorating/treating cancers with elevated MCR-1, including melanoma and mesothelioma.
Preventing/ameliorating/treating ocular inflammation including dry eye and uveitis.
Preventing/ameliorating/treating ischemia and ischemia-reperfusion.
Preventing/ameliorating/treating circulatory shock, including hemorrhagic, cardiogenic, hypovolemic, and vasodilatory forms.
Use in melanocortin receptor-mediated disease via administering a pharmaceutical composition containing the claimed cyclic peptide or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier in a human or non-human mammal.
Treatment of a condition that responds to changes in melanocortin receptor function by administering the pharmaceutical composition containing the claimed cyclic peptide or pharmaceutically acceptable salt and a pharmaceutically acceptable carrier to a mammal.
Cytokine and/or growth factor responsive cancers, including pleural mesothelioma expressing MCR-1 receptor protein.
Ocular inflammatory diseases including dry eye disease and uveitis.
Ischemia and ischemia-reperfusion injuries including renal ischemia and organ transplant perfusion, including neuroprotection.
Circulatory shock, including Stage I–III shock; hemorrhagic shock; cardiogenic shock; vasodilatory shock; septic shock/bacteremic shock; and hypovolemic shock.
Targeted imaging for melanoma and other MCR-1-high conditions using radionuclide-conjugated peptides, including gamma emitter and positron emitter examples.
Cytotoxic therapy for melanoma and other MCR-1-high conditions using peptide-linked chemotherapeutic agents and/or radiation therapeutic agents and/or toxins via linkers/chelation.
Combination therapy described for use with anti-inflammatory agents and phosphodiesterase (PDE) inhibitors targeting cAMP, including ocular combination therapies.
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