Design, synthesis, and structure-activity relationships of a series of 3-[2-(1-benzylpiperidin-4-yl)ethylamino]pyridazine derivatives as acetylcholinesterase inhibitors

Starting from the 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-6-phenylpyridazi ne 1, we performed the design, the synthesis, and the structure-activity re lationships of a series of pyridazine analogues acting as AChE inhibitors. Structural modifications were achieved on four different parts of compound I and led to the following observations: (i) introduction of a lipophilic e nvironment in the C-5 position of the pyridazine ring is favorable for the AChE-inhibitory activity and the AChE/BuChE selectivity; (ii) substitution and various replacements of the C-6 phenyl group are possible and led to eq uivalent or slightly more active derivatives; (iii) isosteric replacements or modifications of the benzylpiperidine moiety are detrimental to the acti vity. Among all derivatives prepared, the indenopyridazine derivative 4g wa s found to be the more potent inhibitor with an IC50 of 10 nM on electric e el AChE. Compared to compound 1, this represents a 12-fold increase in pote ncy. Moreover, 3-[2-(1-benzylpiperidin-4-yl)-ethylamino]-5-methyl-6-phenylp yridazine 4c, which showed an IC50 of 21 nM, is 100-times more selective fo r human AChE (human BuChE/AChE ratio of 24) than the reference compound tac rine.