Glucagon-like peptide-1 (GLP-1R) receptor agonists comprise a growing class of agents that deliver unprecedented efficacy in diabetes.  Members of the class are also approved or under development for obesity and show further promise for the treatment of non-alcoholic steatohepatitis (NASH). GLP-1 is a 30 amino acid peptide hormone that activates the GLP-1 receptor, a class B GPCR that is particularly challenging to stimulate with small molecules. Recently, Pfizer disclosed the structure of the orally bioavailable, small molecule, GLP-1R agonist PF-06882961 (danuglipron), which is currently undergoing clinical trials.  This presentation will discuss the synthetic strategy toward PF-06882961 from mg scale parallel medicinal chemistry to kg scale for pre-clinical safety studies. Large scale amenable routes to the three key fragments (amino-oxetane, 4-pyridyl-piperdine and benzimidazole) will be highlighted with a focus on the discovery of a novel hydrolysis transformation utilizing an organic base in the penultimate step.

Discovery and synthesis of danuglipron (PF-06882961): A small molecule GLP-1 receptor agonist– from lead to clinical candidate

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