1. Fragment-based design of 3-aminopyridine-derived amides as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).
- Author
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Dragovich PS, Zhao G, Baumeister T, Bravo B, Giannetti AM, Ho YC, Hua R, Li G, Liang X, Ma X, O'Brien T, Oh A, Skelton NJ, Wang C, Wang W, Wang Y, Xiao Y, Yuen PW, Zak M, Zhao Q, and Zheng X
- Subjects
- Amides chemistry, Aminopyridines chemistry, Aminopyridines pharmacology, Antineoplastic Agents chemical synthesis, Antineoplastic Agents chemistry, Antineoplastic Agents pharmacology, Cell Proliferation drug effects, Cells, Cultured, Crystallography, X-Ray, Enzyme Activation drug effects, Enzyme Inhibitors chemistry, Humans, Inhibitory Concentration 50, Models, Molecular, Structure-Activity Relationship, Amides chemical synthesis, Amides pharmacology, Aminopyridines chemical synthesis, Cytokines antagonists & inhibitors, Enzyme Inhibitors chemical synthesis, Enzyme Inhibitors pharmacology, Nicotinamide Phosphoribosyltransferase antagonists & inhibitors
- Abstract
The fragment-based identification of two novel and potent biochemical inhibitors of the nicotinamide phosphoribosyltransferase (NAMPT) enzyme is described. These compounds (51 and 63) incorporate an amide moiety derived from 3-aminopyridine, and are thus structurally distinct from other known anti-NAMPT agents. Each exhibits potent inhibition of NAMPT biochemical activity (IC50=19 and 15 nM, respectively) as well as robust antiproliferative properties in A2780 cell culture experiments (IC50=121 and 99 nM, respectively). However, additional biological studies indicate that only inhibitor 51 exerts its A2780 cell culture effects via a NAMPT-mediated mechanism. The crystal structures of both 51 and 63 in complex with NAMPT are also independently described., (Copyright © 2013 Elsevier Ltd. All rights reserved.)
- Published
- 2014
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