molecules of the month


oral GLP-1R class B GCPR agonist

oral glucose-lowering activity observed in HV

from sensitized cell HTS of 2.8M cmpds + opt.

bioRxiv, Sep. 30, 2020

Pfizer, Cambridge, MA / Groton, CT

Structure of PF-06882961, an oral small molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R)
1 min read

PF-06882961 is an oral small molecule agonist of the glucagon-like peptide-1 receptor (GLP-1R). GLP-1R agonists increase the production of insulin and are highly useful in the treatment of diabetes. However, until the recent introduction of an oral formulation of semaglutide, GLP-1 agonists were all peptides requiring inconvenient injections. Small molecule agonists with convenient oral dosing are therefore desirable, but have been difficult to identify despite significant industry effort. The Pfizer team was able to identify weak agonist starting points (~70% @ 20 uM) using an innovative positive allosteric modulator-sensitized cell-based assay, which they would not have identified without sensitization. Significant optimization led to the ~100,000x more potent agonist PF-06882961 (13 nM in non-sensitized cell line). Despite additional challenges including the fact…

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