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

Zhengnan Shen, Kiira Ratia, Isabella Krider, Martha Ackerman-Berrier, Christopher Penton, Soumya Reddy Musku, Jesse M. Gordon-Blake, Megan S. Laham, Nicholas Christie, Nina Ma, Jiqiang Fu, Rui Xiong, Jenna M. Courey, Ganga Reddy Velma, Gregory R.J. Thatcher

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)16704-16727
Number of pages24
JournalJournal of Medicinal Chemistry
Volume66
Issue number24
DOIs
StatePublished - Dec 28 2023

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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