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-phenylpyridazine 1, we performed the design, the synthesis, and the structure-activity relationships of a series of pyridazine analogues acting as AChE inhibitors. Structural modifications were achieved on four different parts of compound 1 and led to the following observations: (i) introduction of a lipophilic environment 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 equivalent or slightly more active derivatives; (iii) isosteric replacements or modifications of the benzylpiperidine moiety are detrimental to the activity. Among all derivatives prepared, the indenopyridazine derivative 4g was found to be the more potent inhibitor with an IC(50) of 10 nM on electric eel AChE. Compared to compound 1, this represents a 12-fold increase in potency. Moreover, 3-[2-(1-benzylpiperidin-4-yl)ethylamino]-5-methyl-6-phenylpyridazine 4c, which showed an IC(50) of 21 nM, is 100-times more selective for human AChE (human BuChE/AChE ratio of 24) than the reference compound tacrine.
Contreras
J M
JM
Laboratoire de Pharmacochimie de la Communication Cellulaire, UMR 7081 du CNRS, Université Louis Pasteur, Faculté de Pharmacie, 74, route du Rhin, 67401 Illkirch Cedex, France.
Parrot
I
I
Sippl
W
W
Rival
Y M
YM
Wermuth
C G
CG
D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D015195:Drug Design; D004593:Electrophorus / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry; D011724:Pyridazines / Q000138:chemical synthesis* / Q000737:chemistry; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014101:Torpedo / Q000378:metabolism
C433819:3-(2-(1-benzylpiperidin-4-yl)--ethylamino)-5-methyl-6-phenylpyridazine; C433818:3-(2-(1-benzylpiperidin-4-yl)-ethylamino)-5H-indeno(1,2-c)pyridazine; D002800:Cholinesterase Inhibitors; D010880:Piperidines; D011724:Pyridazines; D011725:Pyridines; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase