Minimizing CYP2C9 Inhibition of Exposed-Pyridine NAMPT (Nicotinamide Phosphoribosyltransferase) Inhibitors

NAMPT
inhibitors may show potential as therapeutics for oncology. Throughout
our NAMPT inhibitor program, we found that exposed pyridines or related
heterocyclic systems in the left-hand portion of the inhibitors are
necessary pharmacophores for potent cellular NAMPT inhibition. However,
when combined with a benzyl group in the center of the inhibitors,
such pyridine-like moieties also led to consistent and potent inhibition
of CYP2C9. In an attempt to reduce CYP2C9 inhibition, a parallel synthesis
approach was used to identify central benzyl group replacements with
increased Fsp3. A spirocyclic central motif was thus discovered that
was combined with left-hand pyridines (or pyridine-like systems) to
provide cellularly potent NAMPT inhibitors with minimal CYP2C9 inhibition.
Further optimization of potency and ADME properties led to the discovery
of compound 68, a highly potent NAMPT inhibitor with
outstanding efficacy in a mouse tumor xenograft model and lacking
measurable CYP2C9 inhibition at the concentrations tested.