Melanocortin-1 receptor-specific cyclic hexapeptides
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Publication Number
US-10017539-B2
Publication Date
2018-07-10
Expiration Date
Abstract
Melanocortin receptor-specific cyclic hexapeptides of the formula where R1, R2, R3, R4, R5, R6, R7, R8 and R9 are as defined in the claims, compositions and formulations including the hexapeptides 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 patent describes melanocortin-1 receptor (MC-1/MCR-1)-specific cyclic hexapeptides as MCR-1 agonist pharmaceuticals. The cyclic hexapeptides are defined by formula (I), include all enantiomers, stereoisomers or diastereoisomers thereof, and include pharmaceutically acceptable salts, with variable substituent and ring-forming constraints across the structure.
The disclosed cyclic hexapeptides include selected Ac-Nle-cyclo(Glu/Orn/Pro-D-Phe(aryl)-Arg-Dab)-NH2 sequences, including variants containing Pro or Orn and Phe substituted with halogen or substituted groups such as 2-Cl, 3-Cl, 4-Cl, 2-F, 4-F, 3,4-F, 4-Me, and 4-OMe. The core cyclic peptide design is based on a His-Phe-Arg-derived core, excluding Trp from within the cyclic portion while placing Trp or an aryl or heteroaryl mimetic such as Nal1 or Nal2 immediately outside the cyclic portion on the C-terminal side.
The patent additionally provides definitions and terminology for amino acid-related groups used in the cyclic hexapeptide structures, including Nle and D-isomers, α,α-disubstituted amino acids such as Aib and N-substituted amino acids such as sarcosine. The description includes receptor binding and functional assay results for multiple specific cyclic hexapeptides, including MC-4 Ki and MC-1 Ki values, and cAMP potency and efficacy readouts such as MC-1 cAMP EC50, cAMP HBL EC50, and MC-1 Emax.
Claims Coverage
The claim coverage includes two independent claims: one broad structural Markush-defined cyclic hexapeptide of formula (I) and one independent claim selecting specific named cyclic hexapeptides by sequence. Overall coverage spans a structural peptide definition with extensive variable substituents and stereoisomer/salt forms, and a specific sequence-selected cyclic hexapeptide set with pharmaceutically acceptable salts, with dependent claim coverage for pharmaceutical compositions and treatment uses.
Formula (I) cyclic hexapeptide with variable ring-forming and substituent definitions
A cyclic hexapeptide of formula (I) including all enantiomers, stereoisomers or diastereoisomers thereof, or a pharmaceutically acceptable salt of any of the foregoing, with defined variable substituent options and ring-forming constraints across the structure.
Selected cyclic hexapeptides defined by named Ac-Nle-cyclo(Glu/Orn/Pro)-Phe-Arg-Dab sequences
A cyclic hexapeptide selected from the group consisting of Ac-Nle-cyclo(Glu-His-D-Phe-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-His-D-Phe-Ala-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(2-Cl)-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(3-Cl)-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(4-Cl)-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(2-F)-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(4-F)-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(3,4-F)-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(4-Me)-Arg-Dab)-NH2, Ac-Nle-cyclo(Glu-Orn-D-Phe(4-OMe)-Arg-Dab)-NH2, and Ac-Nle-cyclo(Glu-Pro-D-Phe-Arg-Dab)-NH2, or a pharmaceutically acceptable salt of any of the foregoing.
The claim coverage is anchored by a broad structural formula claim for a cyclic hexapeptide of formula (I) with defined variable substituents and ring-forming rules, together with a separate independent claim enumerating specific Ac-Nle-cyclo(Glu-...)-NH2 sequences and their pharmaceutically acceptable salts. Dependent claims further cover pharmaceutical compositions with a pharmaceutically acceptable carrier and treatment by administration for melanocortin receptor-mediated diseases or conditions responsive to changes in melanocortin receptor function.
Stated Advantages
Selectivity toward MC-1 relative to MC-4 is supported by generally low MC-1 Ki values while MC-4 Ki is much higher for multiple variants.
Functional MC-1 cAMP signaling activity is reported with variant-dependent EC50 values and Emax values reported within approximately 86% to 102%.
Documented Applications
Treatment of a melanocortin receptor-mediated disease in a mammal by administering the pharmaceutical composition.
Treatment of a condition responsive to changes in melanocortin receptor function in a mammal by administering the pharmaceutical composition.
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