Identification of Novel Triazole-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors Endowed with Antiproliferative and Antiinflammatory Activity

Cristina Travelli, Silvio Aprile, Reza Rahimian, Ambra A. Grolla, Federica Rogati, Mattia Bertolotti, Floriana Malagnino, Rosanna Di Paola, Daniela Impellizzeri, Roberta Fusco, Valentina Mercalli, Alberto Massarotti, Giorgio Stortini, Salvatore Terrazzino, Erika Del Grosso, Gohar Fakhfouri, Maria Pia Troiani, Maria Alessandra Alisi, Giorgio Grosa, Giovanni SorbaPier Luigi Canonico, Giuseppe Orsomando, Salvatore Cuzzocrea, Armando A. Genazzani, Ubaldina Galli, Gian Cesare Tron

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Abstract

Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme involved in the recycling of nicotinamide to maintain adequate NAD levels inside the cells. It has been postulated to be a pharmacological target, as it is overexpressed in cancer cells as well as in inflammatory diseases. We describe the synthesis and characterization of a novel class of one-digit nanomolar NAMPT inhibitors based on in vitro characterization. The most active compound tested, 30c, displayed activity in xenograft and allograft models, strengthening the potential of NAMPT inhibitors as antitumoral drugs. Furthermore, in the present contribution we describe the ability of 30c to significantly improve the outcome of colitis in mice. Given that this is the first report of an effect of NAMPT inhibitors in colitis, this result paves the way for novel applications for this class of compounds.

Lingua originaleInglese
pagine (da-a)1768-1792
Numero di pagine25
RivistaJournal of Medicinal Chemistry
Volume60
Numero di pubblicazione5
DOI
Stato di pubblicazionePubblicato - 9 mar 2017

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