Modulators of G-protein coupled receptors

Inventors

Erlanson, Daniel • FUCINI, Raymond V. • Hansen, Stig • Iwig, Jeff • KRISHNAN, Shyam • Moya, Enrique • Sethofer, Steven

Assignees

Carmot Therapeutics Inc

Abstract

This disclosure features chemical entities (e.g., a compound or a pharmaceutically acceptable salt) that modulate (e.g., agonize or partially agonize or antagonize) glucagon-like peptide-1 receptor (“GLP-1R”) and/or the gastric inhibitory polypeptide receptor (“GIPR”). The chemical entities are useful, e.g., for treating a disease, disorder, or condition in which modulation (e.g., agonism, partial agonism or antagonism) of GLP-1R and/or GIPR activities is beneficial for the treatment or prevention of the underlying pathology and/or symptoms and/or progression of the disease, disorder, or condition. In some embodiments, modulation results in enhancement of (e.g., increases) existing levels (e.g., normal or below normal levels) of GLP-1R and/or GIPR activity (e.g., signaling). In some embodiments, the chemical entities described herein further modulate (e.g., attenuate, uncouple) β-arrestin signaling relative to what is observed with the native ligand. This disclosure also features compositions as well as other methods of using and making the said chemical entities.

Core Innovation

The disclosed subject matter provides peptide-linked compound frameworks defined by broad structural formulas, sequence identifiers, and variable substituent groups. The framework includes peptide-based chemical entities that modulate GLP-1R and/or GIPR, with agonist, partial agonist, and/or antagonist forms, and with receptor modulation linked to specific intracellular signaling outcomes.

A key theme is enhancing cAMP signaling while attenuating β-arrestin coupling, described as uncoupling relative to native ligands. The disclosure ties this signaling bias to reducing GLP-1R/GIPR-related aversion, including conditioned taste aversion described as associated with nausea risk, and contrasts β-arrestin coupling disruption with non-β-arrestin GPCR signaling complexes as the mechanistic basis for the desired outcome.

The content further defines compound embodiments by Formula (I), Formula (A), and related W group structures, including specific sequence embodiments, variable substituent options, and peptide-linked structures identified by SEQ ID NO references. It also includes pharmaceutical compositions comprising the compound or pharmaceutically acceptable salt with pharmaceutically acceptable excipients, together with labeled chemical structure depictions and associated file/image identifiers.

The patent also describes multiple example chemical structures, each associated with stated elemental composition and mass/ion values. The structures are organized into sequence labels and shared core motifs, including aryl–quaternary carbon–amide/linked anilide, amide/heterocycle, amide/urea-like, peptidomimetic/amide, and GLP-1/GIP-based fusion or conjugate structures, while substituents vary between the examples.

Claims Coverage

The provided independent claims cover compounds or pharmaceutically acceptable salts selected from defined groups, with dependent claims narrowing scope to specific depicted structures identified by SEQ ID NO references and associated file/image identifiers. Across the claim sets, the inventive features center on selection from defined structural groups, specific peptide-linked or small-molecule embodiments, and in one dependent refinement a pharmaceutical composition with pharmaceutically acceptable excipients.

Overall, the claim coverage is directed to compounds selected from defined groups, with dependents narrowing to specific depicted structures tied to SEQ ID NO references and one formulation refinement to a pharmaceutical composition. The claim language provided does not add additional functional limitations beyond the selection and formulation structure.

Stated Advantages

Documented Applications