Pharmacodynamic and pharmacokinetic profiles of a novel GLP-1 receptor biased agonist-SAL0112.

ABSTRACT

BACKGROUND AND PURPOSE: GLP-1 receptor agonists are clinically utilized for type 2 diabetes and obesity. In vitro and in vivo preclinical studies were performed to assess the druggability of a novel small molecule GLP-1 receptor biased agonist SAL0112. EXPERIMENTAL APPROACH: The HTRF assay, FLIPR assay, TR-FRET assay, and PathHunter assay were utilized for in vitro studies. Liver transporter tests were conducted using the HEK293-OATP1B1 and HEK293-OATP1B3 cell lines. In vitro stability assessments of various species and in vivo PK studies in rodents were performed. A model of type 2 diabetes and obesity induced by a high-energy diet in transgenic C57BL/6 mice expressing the human GLP-1 receptor gene was conducted. PRINCIPAL RESULTS: SAL0112 demonstrated high potency and selectivity in activating the Gαs pathway of the GLP-1 receptor, with no observed desensitization. SAL0112 demonstrated greater stability in human and rat liver microsomes compared to Danuglipron. In vivo PK studies revealed higher absorption of SAL0112 in rats. SAL0112 displayed a significantly lower potential for DDI on liver transporters compared to Danuglipron. SAL0112 led to significant reductions in body weight (P<0.001), blood glucose levels in OGTT (P<0.001), HbA1c (P<0.05) and improved insulin resistance (P<0.01). Notably, it increased peripheral adipocyte density and resolved hepatic steatosis. The efficacy of SAL0112 was found to be comparable to that of Danuglipron and Liraglutide. CONCLUSION: SAL0112 demonstrated potent and selective GLP-1 receptor biased agonism, effectively alleviating signs of type 2 diabetes in a mouse model. These promising findings pave the way for the advancement of SAL0112 into clinical trials.