2-FLUORO-4-PYRIDINYLMETHYL ANALOGS OF LINOPIRDINE AS ORALLY-ACTIVE ACETYLCHOLINE RELEASE-ENHANCING AGENTS WITH GOOD EFFICACY AND DURATION OF ACTION

In an effort to improve the pharmacokinetic and pharmacodynamic proper ties of the cognition-enhancer linopirdine (DuP 996), a number of core structure analogues were prepared in which the 4-pyridyl pendant grou p was systematically replaced with 2-fluoro-4-pyridyl. This strategy r esulted in the discovery of several compounds with improved activity i n acetylcholine (ACh) release-enhancing assays, in vitro and in vivo. The most effective compound resulting from these studies, [(2-fluoro-4 -pyridinyl)methyl]-9(10H)-anthracenone (9), is between 10 and 20 times more potent than linopirdine in increasing extracellular hippocampal ACh levels in the rat with a minimum effective dose of 1 mg/kg. In add ition to superior potency, 9 possesses an improved pharmacokinetic pro file compared to that of linopirdine. The half-life of 9 (2 h) in rats is 4-fold greater than that of linopirdine (0.5 h), and it showed a g -fold improvement in brain-plasma distribution over linopirdine. On th e basis of its pharmacologic, pharmacokinetic, absorption, and distrib ution properties, 9 (DMP543) has been advanced for clinical evaluation as a potential palliative therapeutic for treatment of Alzheimer's di sease.