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

Channeling Nicotinamide Phosphoribosyltransferase (NAMPT) to Address Life and Death

“… 150 Cocrystal structures were obtained for early leads, NP-A1R, NP-A1S, and ZN-2-43S, and for ZN-2-29S obtained from further optimization ( Figure 6 C; Table S3 ). 150 , 151 These structures demonstrated that N-PAMs bind to the rear channel of NAMPT in the absence or presence of NAM ( Figure 7 D). The structure of an N-PAM from a different chemical series, NP-A3, was also obtained, again showing occupancy of the NAMPT rear channel ( Figure 6 C; Table S3 ).…”

“…Optimization of the early lead, NP-A1S, led to syntheses of over 70 analogues . An excellent correlation was observed between binding affinity and potency for enzyme activation.…”

“…We will briefly refer to the carbazole P7C3-A20. , Three labs have independently failed to detect any binding or biochemical activation of recombinant human NAMPT by this compound. ,,, However, in multiple reports, the pharmacological effects of P7C3-A20, including neuroprotection, have been reported as consistent with those predicted for a NAMPT activator. A recent paper reported that treatment of db/db mice (a genetic model of T2D) with P7C3-A20 for 4 weeks “rescued diabetes” .…”

Celebrating the 60th Anniversary of the MIKIW Meeting-in-Miniature: Virtual Special Issue

“…An additional theme of research in this Virtual Special Issue is a focus on allosteric regulation of enzyme activity, which can be a powerful approach to achieve selectivity through both activation and inhibitory mechanisms. In ACS Medicinal Chemistry Letters and the Journal of Medicinal Chemistry , Thatcher and co-workers report the discovery and development of two series of positive allosteric regulators of nicotin­amide phospho­ribosyl­transferase (NAMPT). , These new compounds provide a potential mechanism for addressing loss of NAD+ levels associated with aging and neuro­degenerative diseases. In a separate report, a new ligand­able site for allosteric inhibition of NF-κB-inducing kinase (NIK) was identified, highlighting the power of fragment-based screening for identifying novel enzyme binding sites …”

Nicotinamide Phosphoribosyltransferase Positive Allosteric Modulators Attenuate Neuronal Oxidative Stress

“…Gardell et al described SBI-797812, a “NAMPT booster”; although again, no structure with NAMPT has been published. This line of development led to structurally similar activators. − The phenolic NAT compounds were reported to have neuroprotective activity and, like the NAMPT boosters, activate recombinant NAMPT. , Most recently, our group reported a mechanism of allosteric modulation of NAMPT, along with the discovery of the NP-A1 series of NAMPT-positive allosteric modulators (N-PAMs). , …”