An improved design of water-soluble propofol prodrugs characterized by rapid onset of action.

Background: Phosphate ester prodrugs of propofol (fospropofol, HX0969W) were designed to avoid the unsatisfactory water solubility of the parent drug. However, in previous clinical trials, there were reported prodrug side effects such as paresthesia and pruritus. The accumulation of a phosphate ester component was found to be the main culprit. To exclude this potential risk, we designed 2 amino acid propofol prodrugs (HX0969-Gly-F3, HX0969-Ala-HCl) based on the lead compound (HX0969) by introducing the amino acid group into the structures of the propofol prodrugs. We hypothesized that the improved propofol prodrugs could not only eliminate those adverse effects but also retain their rapid action and good water solubility.

Methods: The lead compound HX0969 was synthesized by the sodium borohydride-iodine system. HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl were synthesized from HX0969. The solubility of fospropofol, HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl in normal saline was tested. The bioconversions from those prodrugs to propofol in different physiological media (rat plasma, rhesus monkey plasma, and rat hepatic microsomes) were determined in vitro. An in vivo test in the rats was performed to measure the 50% effective dose (ED50) of the 4 propofol prodrugs. Their action onset time and duration time were also measured after their equipotent doses were given.

Results: (1) The water solubility of fospropofol, HX0969W, HX0969-Gly-F3, and HX0969-Ala-HCl was 461.46 ± 26.40 mg/mL, 189.45 ± 5.02 mg/mL, 49.88 ± 0.58 mg/mL, and 245.99 ± 4.83 mg/mL, respectively; (2) The hydrolysis tests in both the rat plasma and the rhesus monkey plasma revealed that the 2 amino acid prodrugs released propofol to a greater extent at a more rapid rate than the 2 phosphate prodrugs during the testing period of 5 hours. All 4 prodrugs released propofol rapidly in the presence of rat hepatic enzymes; (3) Compared with the previous prodrugs (fospropofol, HX0969W), the 2 novel compounds (HX0969-Gly-F3, HX0969-Ala-HCl) had a much shorter onset time when a much lower dose was given.

Conclusions: Application of the amino acid group to the propofol prodrug can make the prodrug have good water solubility and a more rapid onset of action. In rat plasma, the 2 improved amino acid prodrugs (HX0969-Ala-HCl, HX0969-Gly-F3) had a more rapid rate of propofol release than the 2 phosphate ester prodrugs (fospropofol, HX0969W). The in vivo tests showed that HX0969-Ala-HCl and HX0969-Gly-F3 given IV could have a more rapid onset of action in a smaller dose than fospropofol and HX0969W. This novel design can enhance the efficiency of prodrugs converting to propofol.