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Aminopyridazines as Acetylcholinesterase Inhibitors

1999; American Chemical Society; Volume: 42; Issue: 4 Linguagem: Inglês

10.1021/jm981101z

1520-4804

Jean‐Marie Contreras, Yveline Rival, Saïd Chayer, Jean‐Jacques Bourguignon, Camille G. Wermuth,

Chemical synthesis and alkaloids

Following the discovery of the weak, competitive and reversible acetylcholinesterase (AChE)-inhibiting activity of minaprine (3c) (IC50 = 85 μM on homogenized rat striatum AChE), a series of 3-amino-6-phenylpyridazines was synthesized and tested for inhibition of AChE. A classical structure−activity 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]-6-phenylpyridazine (3y), which shows an IC50 of 0.12 μM on 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