GLP-1R agonists and uses thereof
Inventors
Assignees
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Publication Number
US-10954221-B2
Publication Date
2021-03-23
Expiration Date
Abstract
The present disclosure provides compounds of Formula (I) and pharmaceutical compositions thereof, for use in, e.g. treating type 2 diabetes mellitus, pre-diabetes, obesity, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, and cardiovascular disease.
Core Innovation
The disclosure is directed to structure-defined GLP-1 receptor agonist compounds represented by Formula I and related structural formulae, together with pharmaceutically acceptable salts and compositions. The compounds are described with multiple structural embodiments, including multi-ring scaffold variations, stereoisomers, solvates, and hydrates, and are framed within the described structural formulae.
A key technical theme is GLP-1R biased or partial agonism. The compounds function as full agonists for GLP-1R-mediated cAMP signaling while acting as partial agonists for β-arrestin recruitment compared with GLP-1 (7–37), with the stated goal of sustained GLP-1R signaling with reduced GI side effects.
The disclosure further includes assay characterization intended to distinguish GLP-1R versus β-arrestin recruitment behavior in relation to cAMP signaling. The described assay types include GLP-1R/β-arrestin recruitment, internalization, NanoBit, and cAMP assays, including comparison to GLP-1 (7–37) and reference to β-arrestin (arrestin-2).
The disclosure characterizes structurally defined benzimidazole-related carboxylic acid derivatives, including substituted (S)-benzo[d]imidazole carboxylic acid derivatives, benzimidazole/imidazo[4,5-b]pyridine carboxylic acid analogs, and thiazole/isothiazole-containing benzimidazole carboxylic acid derivatives. The description provides extensive analytical characterization using LCMS (M+H), retention time, and 1H NMR data, and it includes multiple specific compound examples.
Claims Coverage
The provided independent claims are directed to structure-defined GLP-1R agonist compounds, or pharmaceutically acceptable salts thereof, and to pharmaceutical compositions comprising a pharmaceutically acceptable excipient and the same class of structure-defined compounds. Across the independent claims, the inventive coverage is centered on the compound structure and the composition format, with four independent claim formulations present in the source items.
Structure-defined GLP-1 receptor agonist compound
A compound or a pharmaceutically acceptable salt thereof, wherein the compound is represented by the following structure.
Pharmaceutical composition with excipient and structure-defined GLP-1 receptor agonist compound
A pharmaceutical composition comprising a pharmaceutically acceptable excipient, and a compound represented by the following structure or a pharmaceutically acceptable salt thereof.
Structurally defined compound or pharmaceutically acceptable salt
A compound or a pharmaceutically acceptable salt thereof; wherein the compound is represented by a specified structure.
Pharmaceutical composition with pharmaceutically acceptable excipient and structurally defined compound
A pharmaceutical composition comprising a pharmaceutically acceptable excipient, and a compound represented by a specified structure or a pharmaceutically acceptable salt thereof.
The independent claims collectively cover structure-defined GLP-1R agonist compounds, or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising a pharmaceutically acceptable excipient together with those same compounds. The inputs also identify substituted benzo[d]imidazole carboxylic acid derivatives, benzimidazole/imidazo[4,5-b]pyridine carboxylic acid analogs, and thiazole/isothiazole-linked benzimidazole carboxylic acid derivatives as examples within the disclosed scope.
Stated Advantages
The compounds aim for sustained signaling with reduced GI side effects.
Supports successful synthesis/identity across multiple analogs through extensive LCMS and 1H NMR characterization.
Documented Applications
Prevention and treatment of cardiometabolic diseases including type 2 diabetes, pre-diabetes, obesity, NASH, and cardiovascular disease.
Pharmaceutical compositions comprising a pharmaceutically acceptable excipient and the structurally defined compounds or pharmaceutically acceptable salts.
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