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Nat Neurosci 5

doi: 10.1016/j.eururo.2018.09.030 42 OhMHSunIHZhaoLLeoneRDSunIMXuWet al

Discovery of Bisubstrate Inhibitors of Nicotinamide N-Methyltransferase (NNMT)

wherein the ligand is selected from the group consisting of: glutathione, S-(p-bromobenzyl)glutathione, gamma-(L-gamma-azaglutamyl)-S-(p-bromobenzyl)-L-cysteinylglycin, S-butylglutathione, S-decylglutathione, glutathione reduced ethyl ester, glutathionesulfonic acid, S-hexylglutathione, S-lactoylglutathione, S-methylglutathione, S-(4-nitrobenzyl)glutathione, S-octylglutathione, S-propylglutathione, n-butanoyl gamma-glutamylcysteinylglycine, ethanoyl gamma-glutamylcysteinylglycine, hexanoyl gamma-glutamylcysteinylglycine, octanoyl gamma-glutamylcysteinylglycine, dodecanoyl gamma-glutamylcysteinylglycine, GSH monoisopropyl ester (N-(N-L-glutamyl-L-cysteinyl)glycine 1-isopropyl ester sulfate monohydrate) and glutathione derivatives of the formula I:wherein Z=CH 2 and Y=CH 2 , or Z=O and Y = C=O;R 1 and R 2 are independently selected from the group consisting of:i) H,ii) linear or branched alkyl (1-25C),iii) aralkyl (6-26C),iv) cycloalkyl (6-25C),v) heterocycles (6-20C),vi) ethers or polyethers (3-25C), andvii) where R 1 -R 2 together have 2-20C atoms and form a macrocycle with the remainder of formula I;R 3 is selected from the group consisting of H and CH 3 ;R4 is selected form the group consisting of 6-8C alkyl, benzyl, naphthyl and a therapeutically active compound