NAMPT (nicotinamide phosphoribosyltransferase) is an enzyme that catalyzes the rate determining step of an important biosynthetic pathway of NAD, the nicotinamide recycling pathway.  Rapidly proliferating cells such as cancers possess a high metabolic load, with a corresponding high demand for NAD.  As a result, such cells are typically sensitive to mechanisms that reduce the intracellular concentrations of NAD.  NAMPT inhibitors have, therefore, received interest as potential therapeutics for cancer.  A recurring issue in our NAMPT inhibitor program has been potent inhibition of CYP2C9.  We have found that an exposed and nucleophilic pyridine (or related heterocycle) is a prerequisite to obtaining potent cell based inhibition of NAMPT.  We believe the same nucleophilic pyridine (or pyridine-like) moiety required for cell activity is also the pharmacophore for the observed CYP2C9 inhibition.  In this disclosure the mechanistic basis for achieving potent cell based anti-NAMPT activity will be reviewed, and the medicinal chemistry approach that solved the CYP2C9 inhibition issue will be described.  Finally, the preclinical characterization of an optimized NAMPT inhibitor with potent cell based activity and lacking meaningful CYP2C9 inhibition will be disclosed.<br/>

Minimizing CYP2C9 inhibition of exposed-pyridine inhibitors of NAMPT (nicotinamide phosphoribosyltransferase)

251st National Meeting (2016)

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