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

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

  • Eur J Med Chem. 2019 Nov 1:181:111576. doi: 10.1016/j.ejmech.2019.111576.
Cristina Travelli 1,  Silvio Aprile 2,  Daiana Mattoteia 2,  Giorgia Colombo 2,  Nausicaa Clemente 3,  Eugenio Scanziani 4,  Salvatore Terrazzino 2,  Maria Alessandra Alisi 5,  Lorenzo Polenzani 5,  Giorgio Grosa 2,  Armando A Genazzani 2,  Gian Cesare Tron 2,  Ubaldina Galli 6
Affiliations

Affiliations

  • 1 Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy; Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Viale Taramelli 12, 27100, Pavia, Italy.
  • 2 Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy.
  • 3 Dipartimento di Scienze della Salute and IRCAD, Università degli Studi del Piemonte Orientale, Via Solaroli 17, 28100, Novara, Italy.
  • 4 Dipartimento di Medicina Veterinaria, Università degli Studi di Milano, Via Celoria 10, 20133, Milano, Italy; Mouse and Animal Pathology Lab (MAPLab), Fondazione Università degli Studi di Milano, Viale Ortles 22/4, 20139, Milano, Italy.
  • 5 Angelini RR&D (Research, Regulatory & Development), Angelini S.p.A, Piazzale della Stazione Snc, 00071, S. Palomba, Roma, Italy.
  • 6 Dipartimento di Scienze del Farmaco, Università del Piemonte Orientale, Largo Donegani 2, 28100, Novara, Italy. Electronic address: ubaldina.galli@uniupo.it.
PMID: 31400709 DOI: 10.1016/j.ejmech.2019.111576
Abstract

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.

Keywords

Cancer; Click chemistry; Inhibitors; NAD; Nicotinamide phosphoribosyltransferase.

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