Orforglipron is an oral non-peptide glucagon-like peptide-1 (GLP-1) receptor partial agonist that entered Ph. III for obesity and type-2-diabetes mellitus (T2DM). This 2020 and 2023 Molecule of the Year nominee (nominated initially back when it was still in Ph. I) was first discovered by Chugai Pharmaceuticals under the name OWL833, then licensed by Eli Lilly for worldwide development under the name LY3502970. The article discusses where it sits in the GLP-1R agonist landscape, why it’s scientifically notable, how it works with illustrations from cryo-EM structures, its synthesis, and more.

The recently released WHO INN proposed names list includes the structure and name of Structure Therapeutics’ oral small molecule GLP-1R agonist, aleniglipron (GSBR-1290). Seemingly emerging from a “fast-follower” program based on Chugai/Eli Lilly’s orforglipron, the compound includes an unusual phosphine oxide motif and has shown positive results on plasma glucose levels and bodyweight in a Ph. IIa study.

BI-9787 is a potent zwitterionic inhibitor of KHK (ketohexokinase) designed to explore the therapeutic potential of KHK inhibition in metabolic disorders like diabetes, non-alcoholic fatty liver disease, and NASH (non-alcoholic steatohepatitis).

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. [...]

“Compound 10” (AstraZeneca) is an oral CDK5-mediated PPARγ phosphorylation inhibitor and partial PPARγ agonist being developed as an antidiabetic drug . Although widely used PPARγ agonists such as rosiglitazone and pioglitazone are effective antidiabetics, they are limited by [...]