Design, Synthesis, and Structure−Activity Relationships of a Series of 3-[2-(1-Benzylpiperidin-4-yl)ethylamino]pyridazine Derivatives as Acetylcholinesterase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 44; no. 17; pp. 2707 - 2718
• Main Authors: Contreras, Jean-Marie, Parrot, Isabelle, Sippl, Wolfgang, Rival, Yveline M, Wermuth, Camille G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.08.2001; Amer Chemical Soc
• Subjects: Acetylcholinesterase - metabolism; Animals; Biological and medical sciences; Butyrylcholinesterase - metabolism; Chemistry, Medicinal; Cholinergic system; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Drug Design; Electrophorus - metabolism; Life Sciences & Biomedicine; Medical sciences; Models, Molecular; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridines - chemical synthesis; Pyridines - chemistry; Science & Technology; Structure-Activity Relationship; Torpedo - metabolism; TORPEDO-CALIFORNICA; PERIPHERAL SITE; COMPLEX; POTENT; SPECIFICITY; ALZHEIMERS-DISEASE; BIOLOGICAL EVALUATION; ANTAGONISTS; BINDING; MOLECULES; Human; Enzyme; Alzheimer disease; Nitrogen heterocycle; Enzyme inhibitor; Esterases; Selectivity; Acetylcholinesterase; Tricyclic compound; In vitro; Carboxylic ester hydrolases; Structure activity relation; Piperidine derivatives; Hydrolases; Pyridazine derivatives; Aromatic compound; Anticholinesterase agent; Chemical synthesis
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm001088u

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 IC50 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 IC50 of 21 nM, is 100-times more selective for human AChE (human BuChE/AChE ratio of 24) than the reference compound tacrine.