Synthesis and Evaluation of Fluorine-Substituted Phenyl Acetate Derivatives as Ultra-Short Recovery Sedative/Hypnotic Agents

Abstract

BackgroundSoft drugs are molecules that are purposefully designed to be rapidly metabolized (metabolically labile). In anesthesia, the soft drug is useful because it enables precise titration to effect and rapid recovery, which might allow swift and clear-headed recovery of consciousness and early home readiness. Propofol may cause delayed awakening after prolonged infusion. Propanidid and AZD3043 have a different metabolic pathway compared to propofol, resulting in a short-acting clinical profile. Fluorine imparts a variety of properties to certain medicines, including an enhanced absorption rate and improved drug transport across the blood-brain barrier. We hypothesized that the introduction of fluorine to the frame structure of propanidid and AZD3043 would further accelerate the swift and clear-headed recovery of consciousness. To test this hypothesis, we developed a series of fluorine-containing phenyl acetate derivatives.Methodology/Principal FindingsFluorine-containing phenyl acetate derivatives were synthesized, and their hypnotic potencies and durations of LORR following bolus or infusion administration were determined in mice, rats and rabbits. The metabolic half-lives in the blood of various species were determined chromatographically. In vitro radioligand binding and γ-aminobutyric acidA (GABAA) receptor electrophysiology studies were performed. Among the 12 synthesized fluorine-containing phenyl acetate derivatives, compound 5j induced comparable duration of LORR with AZD3043, but more rapid recovery than AZD3043, propanidid and propofol. The time of compound 5j to return to walk and behavioral recovery are approximately reduced by more than 50% compared to AZD3043 in mice and rats and rabbits. The HD50 of compound 5j decreased with increasing animal size.Conclusions/SignificanceThe rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.

Phenyl acetate derivatives, fluorine-substituted on the phenyl group, as rapid recovery hypnotic agents with reflex depression

“…In our previous work [7], we introduced fluorine atoms to the ether (R 1 ) and ester (R 2 ) moieties of the parent structure of propanidid. Among the fluorine-containing phenyl acetate derivatives, compound 1 showed a shorter duration of 'loss of righting reflex' (LORR) and faster recovery time (time to walking and time to behavioral recovery) than propanidid or AZD3043.…”