Tetrahydroisoquinoline-Triazole Derivatives: Novel Nicotinamide N-Methyltransferase Inhibitors

Through the Lilly Open Innovation Drug Discovery program (OIDD), we discovered five cationic bis(aryltriazol-4-yl)methyl)-6,7-dimethoxytetrahydroisoquinolinium derivatives that effectively inhibit human nicotinamide N-methyltransferase. Compounds 4a, 4c, and 4f demonstrated activity against hNNMT in enzymatic-based testing, with IC50 values of 3.177 μM, 7.9 μM, and 4.477 μM, respectively. In cell-based testing, 4c and 4f inhibited the enzyme in HEK293 cells with an IC50 value of 2.81 μM and 1.97 μM. Compound 4m inhibited hNNMT in the enzymatic-based assay by 98% at a concentration of 10 μM, with IC50 of 1.011 μM in the cell-based assay. Through structure-activity relationship analysis, we found that the active compounds had electron-withdrawing substituents at the 4-position of the phenyl-triazole, while compounds containing bulky and electron-donating groups at the same position did not display any activity. The results of docking studies using AutoDock 4.2 showed that all active compounds had similar binding patterns at the NNMT active site. They occupied the nicotinamide binding site and about two-thirds of the S-adenosyl-L-methionine site. However, the SAR and docking results of 4g contradicted the compound’s inactivity. Nevertheless, the molecular docking studies provided insight into how the ligands interact with the protein and explained the activity of our compounds.