Novel [2-(4-piperidinyl)ethyl](thio)ureas: synthesis and antiacetylcholinesterase activity

J Med Chem. 1994 Mar 4;37(5):689-95. doi: 10.1021/jm00031a019.

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.

Publication types

  • Comparative Study

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Amnesia / chemically induced
  • Amnesia / drug therapy
  • Animals
  • Avoidance Learning
  • Cholinesterase Inhibitors / chemical synthesis*
  • Cholinesterase Inhibitors / pharmacology
  • Dementia / drug therapy
  • Dose-Response Relationship, Drug
  • Hydrogen Bonding
  • Mice
  • Molecular Conformation
  • Molecular Structure
  • Piperidines / chemical synthesis*
  • Piperidines / pharmacology
  • Piperidines / therapeutic use
  • Rats
  • Scopolamine
  • Structure-Activity Relationship
  • Thiourea / analogs & derivatives*
  • Thiourea / chemical synthesis
  • Thiourea / pharmacology
  • Thiourea / therapeutic use

Substances

  • Cholinesterase Inhibitors
  • Piperidines
  • 1-(3,4-(methylenedioxy)benzoyl)-3-(2-(1-benzyl-4-piperidinyl)ethyl)thiourea
  • Scopolamine
  • Acetylcholinesterase
  • Thiourea