Scaffold Morphing Identifies 3‑Pyridyl Azetidine Ureas as Inhibitors of Nicotinamide Phosphoribosyltransferase (NAMPT)

Small molecules that inhibit the
metabolic enzyme NAMPT have emerged
as potential therapeutics in oncology. As part of our effort in this
area, we took a scaffold morphing approach and identified 3-pyridyl
azetidine ureas as a potent NAMPT inhibiting motif. We explored the
SAR of this series, including 5 and 6 amino pyridines, using a convergent
synthetic strategy. This lead optimization campaign yielded multiple
compounds with excellent in vitro potency and good ADME properties
that culminated in compound 27.