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Bioorg Med Chem Lett. 2013 Sep 1;23(17):4875-85. doi: 10.1016/j.bmcl.2013.06.090. Epub 2013 Jul 6.

Identification of 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas as potent inhibitors of human nicotinamide phosphoribosyltransferase (NAMPT).

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  • 1Genentech Inc, 1 DNA Way, South San Francisco, California 94080, USA. dragovich.peter@gene.com


Potent nicotinamide phosphoribosyltransferase (NAMPT) inhibitors containing 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived ureas were identified using structure-based design techniques. The new compounds displayed improved aqueous solubilities, determined using a high-throughput solubility assessment, relative to previously disclosed urea and amide-containing NAMPT inhibitors. An optimized 2,3-dihydro-1H-pyrrolo[3,4-c]pyridine-derived compound exhibited potent anti-NAMPT activity (18; BC NAMPT IC50 = 11 nM; PC-3 antiproliferative IC50 = 36 nM), satisfactory mouse PK properties, and was efficacious in a PC-3 mouse xenograft model. The crystal structure of another optimized compound (29; NAMPT IC50 = 10nM; A2780 antiproliferative IC50 = 7 nM) in complex with the NAMPT protein was also determined.

Copyright © 2013 Elsevier Ltd. All rights reserved.


Aqueous solubility; NAMPT; Nicotinamide phosphoribosyltransferase; Tumor metabolism; X-ray crystal structure

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