Identification of potent triazolylpyridine nicotinamide phosphoribosyltransferase (NAMPT) inhibitors bearing a 1,2,3-triazole tail group

• Published in: European journal of medicinal chemistry Vol. 181; p. 111576
• Main Authors: Travelli, Cristina, Aprile, Silvio, Mattoteia, Daiana, Colombo, Giorgia, Clemente, Nausicaa, Scanziani, Eugenio, Terrazzino, Salvatore, Alisi, Maria Alessandra, Polenzani, Lorenzo, Grosa, Giorgio, Genazzani, Armando A., Tron, Gian Cesare, Galli, Ubaldina
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 01.11.2019; Elsevier
• Subjects: Cancer; Chemistry, Medicinal; Click chemistry; Inhibitors; Life Sciences & Biomedicine; NAD; Nicotinamide phosphoribosyltransferase; Pharmacology & Pharmacy; Science & Technology; DMSO; mCPBA; HLM; t-BuOH; EtOH; MTT; Et2O; RLM; THF; HOBt; DMAP; Click chemistry; DMF; TMSN3; PAK4; TMSA; EtOAc; EDCI; NAD; TEA; Inhibitors; MeOH; PE; Nicotinamide phosphoribosyltransferase; Cancer; CYANOGUANIDINE; CELLS; DESIGN; RAT; RETINAL TOXICITY; FK866; DISCOVERY; IN-VITRO
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2019.111576

The enzyme nicotinamide phosphoribosyltransferase is both a key intracellular enzyme for NAD biosynthesis (iNAMPT) and an extracellular cytokine (eNAMPT). The relationship between this latter role and the catalytic activity of the enzyme is at present unknown. With the intent of discovering inhibitors specifically able to target eNAMPT, we increased the polarity of MV78 (EC50 = 5.8 nM; IC50 = 3.1 nM), a NAMPT inhibitor previously discovered by us. The replacement of a phenyl ring with a 1,2,3-triazole bearing a protonable N,N-dialkyl methanamine group gave a series of molecules which maintained the inhibition of the enzymatic activity but were unable to cross the plasma membrane and affect cell viability in vitro. Compounds 30b and 30f can therefore be considered as the first experimental/pharmacological tools for scientists that wish to understand the role of the catalytic activity of eNAMPT. Serendipitously, we also discovered a compound (25) which, notwithstanding its high polarity, was able to cross the plasma membrane being cytotoxic, a potent NAMPT inhibitor and effective in reducing growth of triple negative mammary carcinoma in mice. In our hands, 25 lacked retinal and cardiac toxicity, although we observed a lesser toxicity of NAMPT inhibitors in general compared to other reports. [Display omitted] •Two-digit nanomolar NAMPT inhibitors.•Molecules unable to cross the plasma membrane.•Selectivity on eNAMPT over iNAMPT.•No retinal and cardiac toxicity.