Danuglipron ester prodrugs demonstrate sustained GLP-1R agonism and improved pharmacokinetic potential in human plasma

The glucagon-like peptide-1 receptor (GLP-1R) is a critical target for treating obesity and type 2 diabetes (T2DM). While most approved therapies are peptide-based, small-molecule agonists offer advantages like oral bioavailability. Danuglipron, a small-molecule GLP-1R agonist, showed promise but faced discontinuation in clinical trials due to its short duration of action, significant gastrointestinal side effects, and a potential for drug-induced liver injury. This highlights a crucial gap: the need for small-molecule GLP-1R agonists with improved pharmacokinetic profiles and enhanced safety.

Researchers designed and synthesized a series of novel acid and ester analogs derived from the small-molecule GLP-1R agonist danuglipron. This involved incorporating diverse substitution patterns and deliberate modifications, including variable substitutions and key moiety replacements, to modulate their properties. The synthesized compounds were then evaluated for their in vitro GLP-1R agonistic activity. Crucially, the stability and conversion kinetics of the ester derivatives to their active acid forms were assessed in human plasma using mass spectrometry to determine their potential for sustained systemic exposure.

The synthesized acid forms of danuglipron analogs retained significant GLP-1R agonistic activity, comparable to both the original lead compound, danuglipron, and the established peptide drug tirzepatide. This indicates that the structural modifications did not compromise the essential receptor binding and activation properties. Importantly, one specific ester compound, designated 4, exhibited a controlled and sustained conversion to its active metabolite, 4a, when incubated in human plasma. This sustained conversion was rigorously confirmed through mass spectrometry analysis, which tracked the presence and concentration of the active metabolite over time, alongside in vitro GLP-1R activity assays that verified the metabolite's continued agonistic effect. These findings strongly suggest a favorable pharmacokinetic profile.

Ester compound 4 demonstrated controlled and sustained conversion to its active metabolite 4a in human plasma, confirmed by mass spectrometry and in vitro GLP-1R activity assays.