Aminopyridazines as acetylcholinesterase inhibitors

Following the discovery of the weak, competitive and reversible acetylcholi nesterase (AChE)-inhibiting activity of minaprine (3c) (IC50 = 85 mu M on h omogenized rat striatum AChE), a series of 3-amino-6-phenylpyridazines was synthesized and tested for inhibition of AChE. A classical structure-activi ty relationship exploration suggested that, in comparison to minaprine, the critical elements for high AChE inhibition are as follows: (i) presence of a central pyridazine ring, (ii) necessity of a lipophilic cationic head, ( iii) change from a 2- to a 4-5-carbon units distance between the pyridazine ring and the cationic head. Among all the derivatives investigated, 3-[2-( 1-benzylpiperidin-4-yl)ethylamino] (3y), which shows an IC50 Of 0.12 mu M O n purified AChE (electric eel), was found to be one of the most potent anti -AChE inhibitors, representing a 5000-fold increase in potency compared to minaprine.(1)