Design and\nEvaluation of 3‑Phenyloxetane Derivative\nAgonists of the Glucagon-Like Peptide‑1 Receptor

Various small molecule GLP1R agonists have been developed\nand tested\nfor treating type 2 diabetes (T2DM) and obesity. However, many of\nthese new compounds have drawbacks, such as potential hERG inhibition,\nlower activity compared to natural GLP-1, limited oral bioavailability\nin cynomolgus monkeys, and short duration of action. Recently, a new\ncategory of 3-phenyloxetane derivative GLP1R agonists with enhanced\nhERG inhibition has been discovered. Using an AIDD/CADD method, compound <b>14</b> (<b>DD202-114</b>) was identified as a potent and\nselective GLP1R agonist, which was chosen as a preclinical candidate\n(PCC). Compound <b>14</b> demonstrates full agonistic efficacy\nin promoting cAMP accumulation and possesses favorable drug-like characteristics\ncompared to the clinical drug candidate Danuglipron. Additionally,\nin hGLP-1R knock-in mice, compound <b>14</b> displayed a sustained\npharmacological effect, effectively reducing blood glucose levels\nand food intake. These findings suggest that compound <b>14</b> holds promise as a future treatment option for T2DM and obesity,\noffering improved properties.