Plasma pharmacokinetic data following administration of compound 22 (i.v. dose of 5 mg/kg and p.o. dose of 20 mg/kg) in rats (n = 6/group).

<p>Plasma pharmacokinetic data following administration of compound 22 (i.v. dose of 5 mg/kg and p.o. dose of 20 mg/kg) in rats (n = 6/group).</p

Structure of compounds 7–26.

<p>Structure of compounds 7–26.</p

Synthesis of compounds 5a-l.

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

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

Synthesis of compounds 7–26.

<p>Synthesis of compounds 7–26.</p

Binding affinities for D₂, D₃, 5-HT_1A, 5-HT_2A, 5-HT_2C and H₁ receptors of compounds 7–26 and reference antipsychotics.^a

a<p>Ki values are taken from three experiments, expressed as means ±SEM.</p>b<p>The Ki values were not calculated because the inhibition percentages at 10 µM were too low.</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

Chemical data of fluorine substituted phenyl acetate derivatives.

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

Title and reference compounds.

<p>Title and reference compounds.</p

In <i>vivo</i> pharmacological profile of compound 22. Inhibition of different behavioral responses after oral administration of the test and reference Compounds.

a<p>95% Confidence limits given in parentheses.</p