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

ABSTRACT: 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

SUBMITTER: Shen Z 

PROVIDER: S-EPMC10758216 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature