Peptide compositions
Inventors
Sharma, Shubh • Van Der Ploeg, Leonardus H. T. • Henderson, Bart
Assignees
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Publication Number
US-10196425-B2
Publication Date
2019-02-05
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 invention relates to isolated polypeptides defined by a structural Formula (I) and pharmaceutically acceptable salts thereof. The polypeptides include variable termini R1 and R2 and specific residue positions A1 through A8, with the presence or absence of certain residues permitted. The structure further specifies selected residue identities for A1, A3, A4, A5, A6, and A7, while A2 and A8 are selected from residues able to form a covalent bond between their respective side chains.
The structural Formula (I) allows flexibility in termini definitions, including R1 being either —H or a C1–C6 acyl and R2 being either —NR3R4 or —OR5, with R3, R4, and R5 each independently being H or a C1–C6 alkyl. The invention additionally defines allowable side-chain and structural options for A1, including specified amino-acid residues and optional substituted alkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl moieties. Residues may be either in L- or D-configuration, subject to explicit stereochemical constraints.
A2 and A8 are each selected to form a covalent bond between their side chains, selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr. The invention imposes multiple compatibility conditions across the structure, including restrictions on which combinations of A3, A4, and stereochemical forms are allowed, and further restrictions that apply depending on which residue classes are chosen for A2 and A8. These constraints define the resulting class of MC4R modulators as isolated polypeptides while maintaining the specified structural framework of Formula (I).
Claims Coverage
The independent claims cover isolated polypeptides of structural Formula (I), with variable termini R1 and R2, enumerated residue or moiety options at positions A1 and A3–A5, fixed A6 Arg and A7 Trp, and explicit stereochemical and side-chain covalent-bond compatibility constraints for A2 and A8. The excerpt also includes pharmaceutically acceptable salts and a pharmaceutical composition including a pharmaceutically acceptable carrier.
Isolated polypeptide defined by structural Formula (I)
An isolated polypeptide of structural Formula (I) or a pharmaceutically acceptable salt thereof, with R1 being —H or a C1–C6 acyl; R2 being —NR3R4 or —OR5 with R3, R4, and R5 independently H or a C1–C6 alkyl; defined selectable amino-acid residues or moieties at positions A1, A3, A4, and A5; fixed A6 Arg and A7 Trp; and A2 and A8 selected from residues able to form a covalent bond between their respective side chains, with explicit restrictions on allowable combinations and L- or D-configuration.
Covalent side-chain bond pairing between positions A2 and A8
A2 and A8 are each independently selected from Cys, hCys, Pen, Asp, Glu, Lys, Orn, Dbu, or Dpr, and A2 and A8 are pairwise selected so as to be able to form covalent bond between their respective side chains, subject to further structural compatibility conditions tied to identities or absence of A3 and A4 and to the residue classes selected for A2 and A8.
Stereochemical and combination constraints across A3 and A4
Any amino-acid residue is either in L- or in D-configuration, with constraints that include that A3 and A4 are not both absent; that when A4 is an amino acid, A3 is not Aib or Gly; that when A4 is unsubstituted His and A5 is unsubstituted D-Phe or 2-Nal, A3 is not a D-amino acid or L-Ala; and additional rules depending on whether A2 and A8 are selected from Cys, hCys, or Pen, as well as restrictions when A2 is Asp, Glu, Lys, or Orn.
The claims define a structurally bounded class of isolated polypeptides by Formula (I), centered on the termini framework R1 and R2, the allowed residue and moiety choices at A1 and A3–A5, fixed A6 Arg and A7 Trp, a requirement that A2 and A8 be selected to form a covalent side-chain bond, and multiple stereochemical and compatibility restrictions across the allowed residue and absence combinations.
Stated Advantages
Higher selectivity/potency for MC4R and MC3R versus MC1R.
Reduced side effects associated with blood pressure, heart rate, sexual arousal, and skin pigmentation.
Documented Applications
Treating MC4R-responsive disorders by administering an effective amount, including obesity, type 1 diabetes, type 2 diabetes, insulin resistance, and metabolic syndrome.
Treating additional MC4R-responsive conditions referenced as psychiatric, sexual, inflammatory, and metabolic conditions.
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