YL]ETHYL]-6H-PYRROLO[3,2-F]-1,2-BENZISOXAZOL-6-ONE - A POTENT AND CENTRALLY-SELECTIVE INHIBITOR OF ACETYLCHOLINESTERASE WITH AN IMPROVED MARGIN OF SAFETY

A series of N-benzylpiperidines (2a-d, 10) with novel isoxazole-contai ning tricycles has been prepared. This series has shown potent in vitr o inhibition of the enzyme acetylcholinesterase (AChE), with IC(50)s = 0.33-3.6 nM. Compound 2a was the most potent inhibitor with an IC50 = 0.33 +/- 0.09 nM. Derivatives 2a-d and 10 displayed weak in vitro inh ibition of butyrylcholinesterase (BuChE) with IC(50)s = 600-23 000 nM. The most selective compound was 2a with a BuChE/AChE ratio in excess of 4 orders of magnitude (>10 000). Pyrrolobenzisoxazole 2a also displ ayed a favorable profile in vivo. In microdialysis experiments, 2a pro duced a 200% increase in extracellular levels of acetylcholine (ACh) a t a dose of 0.4 mg/kg in freely moving, conscious rats. Peripheral sid e effects (salivation ED(50) = 26 +/- 1.5 mg/kg) and acute lethality ( LD(50)[1 h] = 42 mg/kg) were observed at >60-fold higher doses. These data indicate that 2a is an AChE inhibitor with good central selectivi ty and a favorable margin of safety. Compound 2a, designated as CP-118 ,954, is currently in clinical development for the treatment of cognit ive disorders.