2230198-02-2

PF-06882961 is a potent, orally bioavailable glucagon-like peptide-1 receptor agonist (GLP-1R) agonist. It has blood glucose lowering and weight loss properties and is used to treat type 2 diabetes (T2D) and obesity.

For example, a methylene-linked oxetane increased potency ~100-fold relative to the methyl substituent of 5, leading to the identification of PF-06882961, which is a full agonist (EC50 = 13 nM) in the CS cAMP assay. PF-06882961 also incorporates a nitrile replacement for the chloride in the benzyl ether region, which served to reduce CLint in HLM as well as in human hepatocytes.
Reference: J Med Chem. 2022 Jun 23;65(12):8208-8226. https://pubmed.ncbi.nlm.nih.gov/35647711/

Intravenous infusion of PF-06882961 during the IVGTT led to an increase in insulin secretion and the rate of glucose disappearance (K-value). Enhancement of glucose-stimulated insulin secretion by PF-06882961 was concentration-dependent and was also observed following oral dosing with similar efficacy when compared to administration by IV infusion. Once-daily administration of PF-06882961 for 2 days also inhibited food intake compared to vehicle-treated monkeys.
Reference: J Med Chem. 2022 Jun 23;65(12):8208-8226. https://pubmed.ncbi.nlm.nih.gov/35647711/

PF-06882961, a non-peptide agonist, activates the canonical G protein signaling activity only in the Glucagon-like peptide-1 (GLP-1) receptor with Trp33ECD.

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