Aminopyridazines as acetylcholinesterase inhibitors.
Following the discovery of the weak, competitive and reversible acetylcholinesterase (AChE)-inhibiting activity of minaprine (3c) (IC50 = 85 microM 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 microM 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
Contreras
J M
JM
Laboratoire de Chimie Organique, ERS 655 du CNRS, Université Louis Pasteur, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch-Cedex, France.
Rival
Y M
YM
Chayer
S
S
Bourguignon
J J
JJ
Wermuth
C G
CG
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D017072:Neostriatum / Q000201:enzymology; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
C117665:3-(2-(1-benzylpiperidin-4-yl)ethylamino)-6-phenylpyridazine; D002800:Cholinesterase Inhibitors; D010880:Piperidines; D011724:Pyridazines; C006149:minaprine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase