title: Synthesis and characterization of novel quick-release propofol prodrug via lactonization.
abstract: The water-soluble derivatives of propofol have gained attention as a method to increase solubility of propofol. According to the principle of lactonization, the lead compound HX0969 was synthesized first and then the pharmacological features of HX0969 were evaluated in a comparison with those of propofol in the SD rats. Then, HX0969 disodium phosphate monoester (HX0969W) and glycine ester trifluoroacetic acid salt (HX101230) were synthesized, and their pharmacological features were compared with those of Lusedra®, which has been recognized and marketed as a water-soluble prodrug of propofol since 2008. The results showed that HX0969 could produce an anesthetic effect within a few seconds (3.6±3.0s) and its therapeutic index was 4.66 in the SD rat. The pharmacodynamic characteristics of HX0969W were similar to those of the Lusedra®. HX101230 could still produce an anesthetic effect within 60s in the rats though its therapeutic index was not so high (TI=2.96). Therefore, our study has indicated that HX0969 is a potentially useful lead compound of propofol derivative. Its rapid anesthetic effect is probably associated with lactonization.
authors: Laboratory of Anesthesia and Critical Care Medicine and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China.
authors: Jun
authors: J
authors: Yang
authors: Wang
authors: W
authors: Yin
authors: Jin
authors: J
authors: Liu
authors: Yu
authors: Y
authors: Wang
authors: Cheng
authors: C
authors: Zhou
authors: Yi
authors: Y
authors: Kang
authors: Wen-Sheng
authors: WS
authors: Zhang
mesh_terms: D018686:Anesthetics, Intravenous / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D006207:Half-Life; D006885:Hydroxybutyrates / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D007783:Lactones / Q000737:chemistry*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D015742:Propofol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012995:Solubility; D014867:Water / Q000737:chemistry
chemical_list: C569054:2,6-diisopropylphenyl-4-hydroxybutanote disodium phosphate; D018686:Anesthetics, Intravenous; C583199:HX0969; D006885:Hydroxybutyrates; D007783:Lactones; D009943:Organophosphorus Compounds; D011355:Prodrugs; D014867:Water; D015742:Propofol