A novel free radical scavenger, nicaraven, inhibits human platelet aggregation in vitro.

The present study was undertaken to investigate whether or not radical scavengers can inhibit platelet aggregation in humans. Toward this end, nicaraven was selected for this study because it has been shown to specifically scavenge hydroxyl radicals that are implicated in platelet aggregation. Ten healthy volunteers and 10 patients with cerebral thrombosis were enrolled in this study. The antiplatelet activities in vitro of nicaraven were examined. The concentrations of nicaraven tested were 3.50 x 10(-5) mol/L, 1.75 x 10(-4) mol/L, 3.50 x 10(-4) mol/L, and 1.75 x 10(-3) mol/L, respectively. The maximum aggregation rate induced by adenosine diphosphate (ADP) was significantly inhibited by nicaraven at concentration ranges of 3.50 x 10(-4) mol/L or higher in the healthy volunteer platelets. The maximum aggregation rate induced by collagen was significantly inhibited by 1.75 x 10(-3) mol/L of nicaraven. Using platelets from patients with cerebral thrombosis, the maximum aggregation rate induced by ADP was significantly inhibited by 1.75 x 10(-3) mol/L of nicaraven. Furthermore, the maximum aggregation rate induced by collagen were significantly reduced by 1.75 x 10(-3) mol/L of nicaraven. Nicaraven induces dose-dependent inhibition of platelet aggregation in both healthy volunteers and patients with cerebral thrombosis.

Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives.

Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain.

Novel piperidine derivatives. Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives.

A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives was synthesized and evaluated for anti-acetylcholinesterase (anti-AChE) activity. Substituting the benzamide with a bulky moiety in the para position led to a substantial increase in activity. Introduction of an akyl or phenyl group at the nitrogen atom of benzamide dramatically enhanced the activity. The basic quality of the nitrogen atom of piperidine appears to play an important role in the increased activity, since the N-benzoylpiperidine derivative was almost inactive. We found that 1-benzyl-4-[2-(N-[4'-(benzylsulfonyl) benzoyl]-N-methylamino]ethyl]piperidine hydrochloride (21) (IC50 = 0.56 nM) is one of the most potent inhibitors of acetylcholinesterase. Compound 21 showed an affinity 18,000 times greater for AChE than for BuChE. At a dose of 3 mg/kg, 21 produced a marked and significant increase in acetylcholine (ACh) content in the cerebral vortex and hippocampus of rats. Compound 21 was chosen for advanced development as an antidementia agent.