Peptide compositions

Inventors

Sharma, Shubh • Van Der Ploeg, Leonardus H. T. • Henderson, Bart

Assignees

Rhythm Pharmaceuticals Inc

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 patent relates to an isolated polypeptide, or a pharmaceutically acceptable salt thereof, having a structural Formula (I). The polypeptide includes defined selections for residues A1 through A8, including A2 and A8 selected from Cys, hCys, Glu, or Dpr such that A2 and A8 are pairwise selected to be able to form a covalent bond between their respective side chains. Formula (I) further defines A1 as H or a C1-C6 acyl, A3 as selected from a defined set or absent, or as a residue Y represented by particular structural formulas, A4 as absent or an optionally substituted His, A5 as an optionally substituted Phe, A6 as Arg, and A7 as Trp.

Any amino acid residue is either in L- or D-configuration, and the residue Y includes substituent possibilities using groups represented by R11, R12, R21-R24, R31-R34, and R41-R43. These structural constraints define a family of covalently cyclized polypeptides consistent with side-chain cyclization between A2 and A8. The disclosed examples include structural variants associated with SEQ ID NOs.

The content further describes receptor binding and functional evaluation against MC4R with selectivity over MC1R using reported performance criteria. The invention provides use of the MC4R modulator for treating MC4R-responsive disorders by administering an effective amount, and it includes context for pharmaceutical compositions, pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

Claims Coverage

The document contains one independent claim defining an isolated polypeptide by structural Formula (I), plus dependent claims that specify particular residue options, add a pharmaceutical composition context, and narrow the polypeptide to specific structural formulas tied to listed SEQ ID NOs. The principal inventive features are the constrained residue selections and the requirement that A2 and A8 be pairwise selected to enable a covalent side-chain bond within the Formula (I) scaffold, while allowing specific substitutions, including residue Y options, and permitting L- or D-configuration for amino acid residues.

Overall, the claim coverage is centered on an isolated polypeptide scaffold defined by structural Formula (I) with covalent side-chain bonding enabled by pairwise selection of A2 and A8, constrained residue identities and substitutions for A3, A4, A5, A6, and A7, and allowance for L- or D-configuration. The dependent claims further narrow the scaffold by adding a pharmaceutical composition context and restricting to particular named structural formulas tied to SEQ ID NOs 21 and 32.

Stated Advantages

Documented Applications