molecules of the month

PF-06835919 is an oral first-in-class clinical candidate for NAFLD/NASH targeting ketohexokinase (KHK), an enzyme which initiates the metabolism of fructose. The authors describe a very elegant structure-based design campaign to improve a modestly active, quickly cleared lead molecule into this highly potent, permeable, bioavailable, and metabolically stable candidate. Key to success included the displacement of a water molecule and removal of three(!) hydroxyl groups from the original lead. It’s interesting that the molecule contains both an azetidine and azabicyclohexane motif, features that were once rare but now seem to be increasingly found in clinical molecules.