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

<div><p>Background</p><p>Soft 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.</p><p>Methodology/Principal Findings</p><p>Fluorine-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. <i>In vitro</i> radioligand binding and γ-aminobutyric acid_A (GABA_A) 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.</p><p>Conclusions/Significance</p><p>The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.</p></div

Specific radioligand binding to off-target receptors by compound 5j (50 µmol).

<p>Data were expressed as the means ± SD.</p

Chemical data of fluorine substituted phenyl acetate derivatives.

<p>Chemical data of fluorine substituted phenyl acetate derivatives.</p

Synthesis of compounds 5a-l.

<p>Synthesis of compounds 5a-l.</p

Recovery of propofol, propanidid, AZD3043, 5J in rabbits after a 20-min or 1-h or 3-h IV infusion.

<p>(A), Duration of LORR. (B), the time to walk. Induction of hypnosis in rabbits was achieved using 2× HD₅₀ dose of test compound, and immediately after induction, infusion via the tail vein was commenced at half the HD₅₀ dosage per min. propofol (1.5 mg·kg⁻¹·min⁻¹; n = 4, 4, or 3, respectively), propanidid (2.5 mg·kg⁻¹·min⁻¹; n = 5, 4, or 5, respectively), AZD3043 (2.4 mg·kg⁻¹·min⁻¹; n = 5, 4, or 5, respectively), 5j (3.0 mg·kg⁻¹·min⁻¹; n = 5, 4, or 5, respectively) in rabbits. *P<0.05 compared with propanidid,^#P<0.05 versus AZD3043, a one-way ANOVA with Dunnett's <i>post hoc</i> test.</p

Hypnotic activities of fluorine substituted phenyl acetate derivatives.

a<p>95% confidence limits. ^bData not available. ^cData not tested. Data was expressed as means ± SD (n = 10).</p

Hypnotic potency of propofol, propanidid and 5j in rabbits.

<p>2× HD₅₀ dose of test compound. Data was expressed as means ± SD (n = 10). ^a95% confidence limits. *P<0.05 versus propanidid; ^#P<0.05 versus AZD3043; a one-way ANOVA with Dunnett's <i>post hoc</i> test.</p

Duration of LORR in mice, rat and rabbit.

<p>2× HD₅₀ administration in mice, rat and rabbit (n = 10 in mice, n = 8 in rat, n = 6 in rabbit for each tested compounds).</p

Hypnotic potency of propofol, propanidid and 5j in rat.

<p>2× HD₅₀ dose of test compound. Data was expressed as means ± SD (n = 10). ^a95% confidence limits. *P<0.05 versus propanidid; ^#P<0.05 versus AZD3043; a one-way ANOVA with Dunnett's <i>post hoc</i> test.</p

The in vitro stability of 5j and AZD3043 in various species.

<p>Data are expressed as means ± SD with respect to the mean t_1/2 values from at least three separate studies.</p><p>*Human whole blood stability experiments were conducted in whole blood from four healthy human donors.</p