Glucagon-like peptide-1 (GLP-1) 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 the class shows 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. To date, all approved agents are large peptide drugs that are administered by injection, negatively impacting both the patient experience and uptake of these highly effective medicines. We will report on a program to identify an oral, small molecule GLP-1 receptor agonist for the treatment of diabetes. An innovative hit identification strategy provided weak leads that were progressed through structure-activity exploration to achieve drug-like potency and ADME attributes, ultimately leading to the identification of PF-06882961 as a clinical candidate.

Discovery of PF-06882961: A potent, orally bioavailable small molecule agonist of the GLP-1 receptor

2019 Spring National Meeting

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