Peptide compositions
Inventors
Sharma, Shubh • Van Der Ploeg, Leonardus H. T. • Henderson, Bart
Assignees
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Publication Number
US-10858399-B2
Publication Date
2020-12-08
Expiration Date
Abstract
The present invention relates to polypeptide compounds that are modulators (e.g., agonists and antagonists) of the melanocortin-4 receptor (MC4R) and pharmaceutical compositions comprising same. The compounds described herein are polypeptide of the following structural Formula (I): or a pharmaceutically acceptable salt thereof. Values and preferred values of the variables in structural Formula (I) are described herein.
Core Innovation
The document discloses MC4R modulators in the form of polypeptide compounds defined by a structural formula (I), including pharmaceutically acceptable salts. The polypeptides include multiple variable positions, including R1, R2, R3, R4, R5 and amino acid residues A1-A8, with permitted residue sets and optional substitutions. The residues can be specified as L- or D-configuration, and multiple compatibility rules constrain which residues may be present or absent together.
A defining feature of the disclosed compounds is that A2 and A8 are each independently selected from specified amino acid residues and are pairwise selected so as to form a covalent bond between their respective side chains. The specification includes covalent-bond-forming residue choices for A2 and A8, including Cys, hCys, and Pen, and further stereochemical and compatibility conditions among other positions, including constraints involving A3, A4, and the combination of A2/A8 residue types.
The compounds are presented for treating a disorder responsive to modulation of the melanocortin-4 receptor (MC4R) by administering an effective amount of the specified polypeptide of structural formula (I) or a pharmaceutically acceptable salt thereof. The disclosed embodiments are characterized as providing improved MC4R potency/selectivity relative to MC1R and mention MC3R, along with reduced side effects such as effects on blood pressure, heart rate, sexual arousal, and skin pigmentation.
Claims Coverage
The independent claim set includes one independent method claim. The claim coverage centers on administering an MC4R-modulating polypeptide of structural formula (I) with defined variable residue sets and specific covalent side-chain cyclization through pairwise A2 and A8 residues, under additional stereochemical and residue-compatibility constraints.
Treating an MC4R-responsive disorder by administering formula (I) polypeptide
A method of treating a disorder responsive to modulation of the melanocortin-4 receptor (MC4R) in a subject in need thereof, comprising administering an effective amount of a polypeptide of structural formula (I) or a pharmaceutically acceptable salt thereof.
Covalent side-chain cyclization via pairwise A2 and A8 residues
A2 and A8 are each independently selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr, wherein A2 and A8 are pairwise selected so as to be able to form covalent bond between their respective side chains, with additional constraints depending on A2/A8 and other residue selections.
Defined amino-acid residue sets and L-/D-configuration with compatibility constraints
A1 is selected from specified amino acid residues or moieties; A3, A4, A5, A6, and A7 are selected from specified sets with A3 optionally absent or defined by residue Y, and any amino acid residue is either in L- or D-configuration, provided that multiple conditions among A3 and A4 and restrictions involving A3, A4, and A2/A8 residue selections are satisfied.
Selected structural variants and SEQ ID NOs
The method uses one of the specified peptide structural formulas and associated SEQ ID NOs, or corresponding cyclized structures identified by those SEQ ID NOs, in combination with pharmaceutically acceptable salts.
Overall claim coverage centers on an MC4R-treatment method that administers a polypeptide of structural formula (I) whose novelty lies in the combined position-specific residue definitions, covalent bond-forming residue pairing at A2 and A8, optional or defined presence of A3 and A4 with structured residue Y/X definitions, and enumerated compatibility rules governing permitted combinations and stereochemistry.
Stated Advantages
Improved MC4R potency/selectivity versus MC1R, and mentions MC3R.
Reduced side effects, including effects on blood pressure and heart rate.
Reduced side effects, including reduced sexual arousal effects and reduced skin pigmentation.
Documented Applications
Treating a disorder responsive to modulation of the melanocortin-4 receptor (MC4R), including obesity, diabetes/insulin resistance, and metabolic syndrome.
Treating additional MC4R-responsive conditions mentioned in the partial content, including non-alcoholic fatty liver disease/steatohepatitis, feeding disorders, cachexia, inflammation, anxiety, erectile dysfunction, female sexual disorder, anorexia/bulimia, cancer cachexia/wasting, and disorders related to substance abuse/alcoholism.
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