Identification of Novel Triazole-Based Nicotinamide Phosphoribosyltransferase (NAMPT) Inhibitors Endowed with Antiproliferative and Antiinflammatory Activity.
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.
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Cristina
C
Travelli
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Silvio
S
Aprile
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran.|Department of Psychiatry and Neuroscience, Faculty of Medicine, Research Center of the Mental Health Institute of Quebec, Laval University , Quebec, Quebec G1J 2G3, Canada.
Reza
R
Rahimian
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Ambra A
AA
Grolla
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Federica
F
Rogati
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Mattia
M
Bertolotti
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Floriana
F
Malagnino
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Via C. Valeria Gazzi, 98100 Messina, Italy.
Rosanna
R
di Paola
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Via C. Valeria Gazzi, 98100 Messina, Italy.
Daniela
D
Impellizzeri
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Via C. Valeria Gazzi, 98100 Messina, Italy.
Roberta
R
Fusco
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Valentina
V
Mercalli
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Alberto
0000-0001-9306-8845
A
Massarotti
Department of Oncology, Nerviano Medical Sciences Srl , Viale Pasteur 10, 20014 Nerviano, Milan, Italy.
Giorgio
G
Stortini
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Salvatore
S
Terrazzino
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Erika
E
Del Grosso
Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences , Tehran, Iran.
Gohar
G
Fakhfouri
R&D, Angelini Research Center, Piazzale della Stazione, 00040 S. Palomba-Pomezia, Italy.
Maria Pia
MP
Troiani
R&D, Angelini Research Center, Piazzale della Stazione, 00040 S. Palomba-Pomezia, Italy.
Maria Alessandra
MA
Alisi
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Giorgio
G
Grosa
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Giovanni
G
Sorba
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Pier Luigi
PL
Canonico
Department of Clinical Sciences (DISCO), Section of Biochemistry, Polytechnic University of Marche , Via Ranieri 67, 60131 Ancona, Italy.
Giuseppe
G
Orsomando
Department of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina , Via C. Valeria Gazzi, 98100 Messina, Italy.
Salvatore
S
Cuzzocrea
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Armando A
AA
Genazzani
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Ubaldina
0000-0003-1126-0142
U
Galli
Dipartimento di Scienze del Farmaco, Università degli Studi del Piemonte Orientale "A. Avogadro" , Largo Donegani 2, 28100 Novara, Italy.
Gian Cesare
GC
Tron
D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D054409:Nicotinamide Phosphoribosyltransferase / Q000037:antagonists & inhibitors*; D013057:Spectrum Analysis / Q000379:methods; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology*
D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D014230:Triazoles; D054409:Nicotinamide Phosphoribosyltransferase