From the *Regenerative Medicine Research Center, West China Hospital of Sichuan University; †Department of Anesthesiology, Laboratory of Anesthesia and Critical Care Medicine, Translational Neuroscience Center, West China Hospital of Sichuan University; and ‡State Key Laboratory of Biotherapy, Sichuan University, Chengdu, Sichuan, People's Republic of China.
Anesth Analg. 2014 Apr;118(4):745-54. doi: 10.1213/ANE.0000000000000124.
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.
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.
(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.
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.
为了避免母体药物不尽人意的水溶性，设计了丙泊酚的磷酸酯前药（磷丙泊酚，HX0969W）。然而，在以前的临床试验中，报告了前药的副作用，如感觉异常和瘙痒。发现磷酸酯成分的积累是主要原因。为了排除这种潜在风险，我们在先导化合物（HX0969）的基础上设计了 2 种氨基酸丙泊酚前药（HX0969-Gly-F3、HX0969-Ala-HCl），通过在前药结构中引入氨基酸基团。我们假设，改进的丙泊酚前药不仅可以消除这些不良反应，还可以保留其快速作用和良好的水溶性。
通过硼氢化钠-碘体系合成先导化合物 HX0969。由 HX0969 合成 HX0969W、HX0969-Gly-F3 和 HX0969-Ala-HCl。测试了磷丙泊酚、HX0969W、HX0969-Gly-F3 和 HX0969-Ala-HCl 在生理盐水的溶解度。在不同的生理介质（大鼠血浆、恒河猴血浆和大鼠肝微粒体）中测定了这些前药转化为丙泊酚的生物转化。在大鼠体内进行了 50%有效剂量（ED50）的测试。在给予等效剂量后，还测量了它们的作用起始时间和持续时间。
（1）磷丙泊酚、HX0969W、HX0969-Gly-F3 和 HX0969-Ala-HCl 的水溶解度分别为 461.46±26.40mg/mL、189.45±5.02mg/mL、49.88±0.58mg/mL 和 245.99±4.83mg/mL；（2）在大鼠血浆和恒河猴血浆的水解试验中，在 5 小时的测试期间，2 种氨基酸前药比 2 种磷酸酯前药以更快的速度更大量地释放丙泊酚。所有 4 种前药在存在大鼠肝酶的情况下都能迅速释放丙泊酚；（3）与以前的前药（磷丙泊酚、HX0969W）相比，当给予更低剂量时，2 种新化合物（HX0969-Gly-F3、HX0969-Ala-HCl）的起始时间更短。
将氨基酸基团应用于丙泊酚前药可以使前药具有良好的水溶性和更快的作用起始时间。在大鼠血浆中，2 种改良的氨基酸前药（HX0969-Ala-HCl、HX0969-Gly-F3）比 2 种磷酸酯前药（磷丙泊酚、HX0969W）释放丙泊酚的速度更快。体内试验表明，静脉注射 HX0969-Ala-HCl 和 HX0969-Gly-F3 比静脉注射磷丙泊酚和 HX0969W 时，在较小剂量下具有更快的作用起始时间。这种新的设计可以提高前药转化为丙泊酚的效率。
