title: Novel [2-(4-piperidinyl)ethyl](thio)ureas: synthesis and antiacetylcholinesterase activity.
abstract: A series of 1-ar(o)yl-3-[2-(1-benzyl-4-piperidinyl)ethyl](thio)urea derivatives was synthesized and evaluated for antiacetylcholinesterase activity. Most aroyl(thio)urea derivatives showed potent inhibitory activity in the sub-micromolar range. A comparable potency was obtained with the aryl(thio)urea analogues by replacing the phenyl with a 2-pyridyl group. The substituted guanidine variations proved to be almost inactive whereas the nitroethylene analogues appeared to be quite efficient. These results were interpreted in terms of the preferential cis-trans conformation of the aroyl(thio)urea and 2-pyridyl(thio)urea moieties involving the existence of hydrogen bonding. In vivo experiments showed that compound 7m had maximal antiamnestic activity at 0.03 mg/kg with a therapeutic ratio greater than 1000, while cholinergic side effects were only seen at doses 100-fold the maximally effective antiamnestic dose. Compound 7m represents a potentially interesting antidementia agent.
authors.affiliation: Division of Medicinal Chemistry, Centre de Recherche Pierre Fabre Médicament, Castres, France.
authors.forename: J L
authors.initials: JL
authors.lastname: Vidaluc
authors.forename: F
authors.initials: F
authors.lastname: Calmel
authors.forename: D
authors.initials: D
authors.lastname: Bigg
authors.forename: E
authors.initials: E
authors.lastname: Carilla
authors.forename: A
authors.initials: A
authors.lastname: Stenger
authors.forename: P
authors.initials: P
authors.lastname: Chopin
authors.forename: M
authors.initials: M
authors.lastname: Briley
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000647:Amnesia / Q000139:chemically induced / Q000188:drug therapy; D000818:Animals; D001362:Avoidance Learning; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D003704:Dementia / Q000188:drug therapy; D004305:Dose-Response Relationship, Drug; D006860:Hydrogen Bonding; D051379:Mice; D008968:Molecular Conformation; D015394:Molecular Structure; D010880:Piperidines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D012601:Scopolamine; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D002800:Cholinesterase Inhibitors; D010880:Piperidines; C086217:1-(3,4-(methylenedioxy)benzoyl)-3-(2-(1-benzyl-4-piperidinyl)ethyl)thiourea; D012601:Scopolamine; D000110:Acetylcholinesterase; D013890:Thiourea