Melanocortin-1 receptor-specific cyclic peptides
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Publication Number
US-9447148-B2
Publication Date
2016-09-20
Expiration Date
Abstract
Melanocortin receptor-specific cyclic peptides of the formula where R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in the specification, compositions and formulations including the peptides of the foregoing formula or salts thereof, and methods of preventing, ameliorating or treating melanocortin-1 receptor-mediated or responsive diseases, indications, conditions and syndromes.
Core Innovation
The document relates to cyclic peptides of formula (I), including all enantiomers, stereoisomers or diastereoisomers thereof, or pharmaceutically acceptable salts of any of the foregoing. The cyclic peptide is defined by substituent variables and ring-forming patterns, including R1, R2, R3, R4, R5, R6, R7, R9, and optional structural variations involving R10, R11, R12, R13, R14, R15, R16, R18, R19a, R19b, and R20, with constraints on chain length and ring-forming assignments for R3/R4 and R6/R7.
The disclosure further describes cyclic peptide realizations within the formula (I) framework, including variants built from cyclo(Glu-His-D-Phe-Arg-Dab) and cyclo(Glu-His-D-Phe-Arg-Dab)-Trp scaffolds. The analogs are differentiated by N-terminal acyl and side-chain modifications, including Ac-Nle and other acyl groups, and by changes between Trp-NH2 and Trp-OH, together with other Trp-related variants such as D-Trp or Nal/NaI1/NaI2 variants and linker changes.
The document also includes pharmacology assay results for the cyclic peptide family, using melanocortin receptor binding and cAMP functional activity. Reported potency/selectivity outcomes include MC-4 Ki, MC-1 Ki, MC-1 EC50, and MC-1 Emax in a cAMP HBL readout or related functional assays, showing variation across the described structural modifications.
Claims Coverage
Across the provided material, the independent claim coverage is centered on cyclic peptides of formula (I) with extensive substituent definitions and stereochemical inclusion. At least one independent structural claim is identified, and the material also describes pharmaceutical composition and method-of-use coverage for melanocortin receptor-mediated disease states in a mammal. In total, three inventive feature groups are present in the consolidated claim coverage.
Cyclic peptide of formula (I) including stereochemical variants
A cyclic peptide of formula (I), including all enantiomers, stereoisomers or diastereoisomers thereof, or a pharmaceutically acceptable salt of any of the foregoing, where the substituent variables and ring-forming assignments are defined by the stated constraints.
Pharmaceutical composition with pharmaceutically acceptable carrier
A pharmaceutical composition comprising the cyclic peptide of the specified structure, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier.
Treatment of melanocortin receptor-mediated disease in a mammal
A method of treating a melanocortin receptor-mediated disease, condition, indication, or syndrome in a mammal by administering the pharmaceutical composition comprising the cyclic peptide and a pharmaceutically acceptable carrier.
The claim coverage centers on the formula (I) cyclic peptide scaffold with defined ring-forming and substituent options, supplemented by pharmaceutical composition coverage and treatment coverage for melanocortin receptor-mediated disease states in mammals.
Stated Advantages
High MCR-1 potency and strong cAMP response are stated in connection with example peptides.
Selectivity indicated by very high MCR-1 potency versus MCR-4 is stated for an example peptide.
Across the set, MC-1 Ki and MC-1 EC50 values show wide potency variation while generally keeping high MC-1 Emax values.
The results show generally high MC-1 potency and relatively strong agonist efficacy, with Emax values often in the approximate range of 90-110%.
Prevents, ameliorates, or treats melanocortin receptor-mediated diseases, conditions, indications, or syndromes.
Potential efficacy is described as spanning a significant dose range.
Non-injection delivery systems are described, including pulmonary administration.
Documented Applications
Treatment of inflammation-related diseases.
Treatment of fibrotic/sclerotic diseases.
Treatment of cytokine-related diseases.
Treatment of ocular diseases including dry eye and uveitis.
Treatment of ischemia and ischemia-reperfusion injury.
Treatment of circulatory shock, including hemorrhagic, cardiogenic, vasodilatory, and hypovolemic forms.
Targeted imaging and cytotoxic therapy for melanoma.
Treating a melanocortin receptor-mediated disease, condition, indication, or syndrome in a mammal by administering the pharmaceutical composition.
Preventing, ameliorating, or treating melanocortin receptor-mediated diseases, conditions, indications, or syndromes in a mammal.
Pulmonary administration and non-injection delivery are described as use or formulation delivery contexts.
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