title: Synthesis and evaluation of fluorine-substituted phenyl acetate derivatives as ultra-short recovery sedative/hypnotic agents.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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. 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
  The rapid recovery might make compound 5j suitable for precise titration and allow swift and clear-headed recovery of consciousness and early home readiness.
authors.affiliation: Systems Biology Theme, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Zhang
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, China.
authors.forename: Xiangqing
authors.initials: X
authors.lastname: Xu
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, China.
authors.forename: Yin
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, China.
authors.forename: Yinli
authors.initials: Y
authors.lastname: Qiu
authors.affiliation: Systems Biology Theme, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Systems Biology Theme, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Bi-Feng
authors.initials: BF
authors.lastname: Liu
authors.affiliation: Systems Biology Theme, Huazhong University of Science and Technology, Wuhan, China; Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou, China.
authors.forename: Guisen
authors.initials: G
authors.lastname: Zhang
mesh_terms: D000085:Acetates / Q000737:chemistry* / Q000493:pharmacokinetics; D000762:Anesthesia Recovery Period; D000818:Animals; D001812:Blood-Brain Barrier; D005461:Fluorine / Q000737:chemistry* / Q000493:pharmacokinetics; D006207:Half-Life; D006993:Hypnotics and Sedatives / Q000737:chemistry / Q000493:pharmacokinetics*; D008297:Male; D051379:Mice; D010636:Phenols / Q000737:chemistry* / Q000493:pharmacokinetics; D011410:Propanidid / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000085:Acetates; D006993:Hypnotics and Sedatives; D010636:Phenols; D005461:Fluorine; C570634:phenyl acetate; D011410:Propanidid