Source of nicotinamide governs its metabolic fate in cultured cells, mice, and humans

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

“…As far as we are aware, this is the only evidence for in vivo NAD+ modulation by a small molecule that increases the activity of recombinant NAMPT. A recent study by Tumpa et al measured NAD + , NMN, NAM, NADH, and related metabolites in cells and in healthy humans, using stable isotopologue LCMS tracers (measurements on SBI-797812 were in cell cultures) . In cells, the NAMPT-booster increased both NAD + production and consumption.…”

“…A recent study by Tumpa et al measured NAD + , NMN, NAM, NADH, and related metabolites in cells and in healthy humans, using stable isotopologue LCMS tracers (measurements on SBI-797812 were in cell cultures). 25 In cells, the NAMPT-booster increased both NAD + production and consumption. This work also proposed that NAD + regulation and NAMPT activation were cell compartment specific, in accord with other studies.…”

“…The organic layer was dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by Prep-HPLC to provide the 8 (41 mg, yield 87%) as a white solid: [α] D 25 ( [3,4-d]pyrimidin-4-yl)piperidine-3-carboxamide (13). ( 13 C NMR (100 MHz, DMSOd 6 ) δ 171.6, 160.9, 157.5, 155.9, 141.…”

“…Both P7C3-A20 and SBI-797812 have shown activity in animal models. Most importantly, the effects of SBI-797812 have been quantified, measuring levels of NAD + (and its metabolites and precursors) in cell cultures and measuring increased NAD + levels in cell cultures and mouse liver tissues . These and other synthetic activators are compared in more detail below.…”

“…Using a similar procedure to the preparation of 8. Light brown solid (yield 87%): [α] D25 = +84.2 (c 0.7, MeOH); 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.34 (s, 1H), 8.49−8.39 (m, 1H), 8.28 (s, 1H), 7.98 (dd, J = 11.0, 2.3 Hz, 1H), 7.88 (dd, J = 8.2, 2.2 Hz, 1H), 7.50 (t, J = 8.4 Hz, 1H), 7.23−7.15 (m, 4H), 5.07−4.43 (m, 2H), 4.30−4.17 (m, 2H), 3.37 (s, 2H), 2.48−2.46 (m, 1H), 2.44 (s, 3H), 2.31 (d, J = 1.8 Hz, 3H), 2.02−1.76 (m, 3H), 1.62−1.47 (m, 1H); 13 C NMR (100 MHz, DMSO-d 6 ) δ 172.4, 160.9, 160.7 (d, J = 243.5 Hz), 157.4, 156.1, 138.5 (d, J = 10.2 Hz), 136.3, 136.2, 132.4 (d, J = 5.9 Hz), 127.9, 126.1, 124.1 (d, J = 17.5 Hz), 123.8, 115.7 (d, J = 2.6 Hz), 107.1 (d, J = 27.7 Hz), 102.5, 46.6, 45.9, 42.2, 41.5, 27.6, 24.3, 14.9, 13.8; HRMS (ESI) calcd for C 26 H 28 FN 6 OS [M + H] + 491.2024, found 491.2032.…”