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. 2024 Sep 12;67(17):14820-14839.
doi: 10.1021/acs.jmedchem.4c01177. Epub 2024 Aug 14.

Design and Evaluation of 3-Phenyloxetane Derivative Agonists of the Glucagon-Like Peptide-1 Receptor

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Design and Evaluation of 3-Phenyloxetane Derivative Agonists of the Glucagon-Like Peptide-1 Receptor

Zhimin Zhang et al. J Med Chem. .

Abstract

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

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