| Identification | Back Directory | [Name]
Nampt-IN-1 | [CAS]
1698878-14-6 | [Synonyms]
Nampt-IN-1
LSN3154567
Nampt inhibitor 1
LSN3154567 (Nampt-IN-1)
LSN 3154567;LSN-3154567;LSN3154567
2-hydroxy-2-methyl-N-[1,2,3,4-tetrahydro-2-[2-(3-pyridinyloxy)acetyl]-6-
2-Hydroxy-2-methyl-N-[1,2,3,4-tetrahydro-2-[2-(3-pyridinyloxy)acetyl]-6-isoquinolinyl]-1-propanesulfonamide
2-hydroxy-2-methyl-N-(2-(2-(pyridin-3-yloxy)acetyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)propane-1-sulfonamide
1-Propanesulfonamide, 2-hydroxy-2-methyl-N-[1,2,3,4-tetrahydro-2-[2-(3-pyridinyloxy)acetyl]-6-isoquinolinyl]- | [Molecular Formula]
C20H25N3O5S | [MDL Number]
MFCD28963946 | [MOL File]
1698878-14-6.mol | [Molecular Weight]
419.49 |
| Chemical Properties | Back Directory | [Boiling point ]
659.9±65.0 °C(Predicted) | [density ]
1.363±0.06 g/cm3(Predicted) | [storage temp. ]
2-8°C | [solubility ]
DMSO: Soluble | [form ]
powder | [pka]
8.67±0.20(Predicted) | [color ]
white to beige | [InChI]
1S/C20H25N3O5S/c1-20(2,25)14-29(26,27)22-17-6-5-16-12-23(9-7-15(16)10-17)19(24)13-28-18-4-3-8-21-11-18/h3-6,8,10-11,22,25H,7,9,12-14H2,1-2H3 | [InChIKey]
QHHSCLARESIWBH-UHFFFAOYSA-N | [SMILES]
[S](=O)(=O)(Nc1cc2c(cc1)CN(CC2)C(=O)COc3cnccc3)CC(O)(C)C |
| Hazard Information | Back Directory | [Description]
Nampt-IN-1 is a potent inhibitor of nicotinamide phosphoribosyltransferase (Nampt; IC50 = 3.1 nM). It is selective for Nampt over a panel of greater than 100 human kinases at 1 μM. Nampt-IN-1 inhibits NAD+ formation in and proliferation of HCT116 cells (IC50s = 1.8 and 8.9 nM, respectively). It inhibits cell growth in a panel of cancer cell lines (IC50s = <0.2-2 μM). Nampt-IN-1 inhibits NAD+ formation in an A2780 ovarian carcinoma mouse xenograft model (ED50 = 2 mg/kg). | [Uses]
Nampt-IN-1 functions as a co-drug. Nampt-IN-1 is a potent and selective NAMPT inhibitor. | [Biochem/physiol Actions]
LSN3154567 might be useful in developing a novel cancer therapeutic. | [in vivo]
Nampt-IN-1 (LSN3154567) exhibits good physical chemical properties that allow oral dosing. When dosed orally with 2 mg/kg in mice, it has an exposure of 195 nM*hour in the plasma with a peak concentration of 57 nM (at 0.25 hour) and an oral bioavailability of 39%. When dosed intravenously with 2 mg/kg, it has a hepatic clearance of 158.73 mL/min/kg and a volume of distribution at 7.1 L/kg. The half-life of terminal elimination is estimated to be 2.76 hours. LSN3154567 exhibits a dose-dependent inhibition of NAD+ formation with estimated TED50 value of 2.0 mg/kg. To assess whether LSN3154567 causes retinopathy, rats are treated with LSN3154567 at 20, 40, and 80 mg/kg for 4 days. No apparent retinopathy is observed. The hematological toxicities are observed. When LSN3154567 is dosed at 20, 40, and 80 mg/kg, the plasma exposures obtained are 8,974, 18,061, and 38,327 M*h, respectively. Thus, LSN3154567 exhibits exposure multiples of respective 3-, 7-, and 14-fold over the exposure (2,701 M*h) required for robust efficacy (≈103%) without NA coadministration. Dogs are treated with LSN3154567 at 1 and 2.5 mg/kg. At these dose levels, the retinal toxicity is observed. Degeneration of the outer nuclear layer occurred in all four animals, but is less pronounced in the animals treated with 1 mg/kg. At the 1 and 2.5 mg/kg dose levels, the plasma exposures are determined to be 1,483 and 2,468 nM*h, respectively[1]. | [References]
[1] GENSHI ZHAO. Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration.[J]. Molecular Cancer Therapeutics, 2017, 16 12: 2677-2688. DOI: 10.1158/1535-7163.mct-16-0674 |
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