Synthesis, Optimization, and Structure–Activity Relationships of Nicotinamide Phosphoribosyltransferase (NAMPT) Positive Allosteric Modulators (N-PAMs)

Depletion of nicotinamide
adenine dinucleotide (NAD+) is associated with aging and
disease, spurring the study of dietary
supplements to replenish NAD+. The catabolism of NAD+ to nicotinamide (NAM) requires the salvage of NAM to replenish
cellular NAD+, which relies on the rate-limiting enzyme
nicotinamide phosphoribosyltransferase (NAMPT). Pharmacological activation
of NAMPT provides an alternative to dietary supplements. Screening
for activators of NAMPT identified small molecule NAMPT positive allosteric
modulators (N-PAMs). N-PAMs bind to the rear channel of NAMPT increasing
enzyme activity and alleviating feedback inhibition by NAM and NAD+. Synthesis of over 70 N-PAMs provided an excellent correlation
between rear channel binding affinity and potency for enzyme activation,
confirming the mechanism of allosteric activation via binding to the
rear channel. The mechanism accounts for higher binding affinity leading
to loss of efficacy. Enzyme activation translated directly to elevation
of NAD+ measured in cells. Optimization led to an orally
bioavailable N-PAM.