Aminopyridazines as Acetylcholinesterase Inhibitors

• Published in: Journal of medicinal chemistry Vol. 42; no. 4; pp. 730 - 741
• Main Authors: Contreras, Jean-Marie, Rival, Yveline M, Chayer, Said, Bourguignon, Jean-Jacques, Wermuth, Camille G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 25.02.1999; Amer Chemical Soc
• Subjects: Acetylcholinesterase - metabolism; Animals; Biological and medical sciences; Butyrylcholinesterase - metabolism; Catecholaminergic system; Chemistry, Medicinal; Cholinesterase Inhibitors - chemical synthesis; Cholinesterase Inhibitors - chemistry; Cholinesterase Inhibitors - pharmacology; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Medical sciences; Neostriatum - enzymology; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Piperidines - chemical synthesis; Piperidines - chemistry; Piperidines - pharmacology; Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease); Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Pyridazines - chemical synthesis; Pyridazines - chemistry; Pyridazines - pharmacology; Rats; Science & Technology; Structure-Activity Relationship; 1,2,4-TRIAZINES; ROUTE; ACID; THERAPY; ALZHEIMERS-DISEASE; POTENT MUSCARINIC AGONISTS; AGENTS; NO CHOLINERGIC SYNDROME; DERIVATIVES; Rat; Enzyme; Alzheimer disease; Nitrogen heterocycle; Rodentia; Central nervous system; Benzene derivatives; Enzyme inhibitor; Esterases; Acetylcholinesterase; In vitro; Carboxylic ester hydrolases; Vertebrata; Mammalia; Structure activity relation; Animal; Piperidine derivatives; Hydrolases; Anticholinesterase agent; Chemical synthesis; Brain (vertebrata)
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm981101z

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.