Sohma Youhei, Hayashi Yoshio, Ito Tomoko, Matsumoto Hikaru, Kimura Tooru, Kiso Yoshiaki
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto 607-8412, Japan.
J Med Chem. 2003 Sep 11;46(19):4124-35. doi: 10.1021/jm030009m.
We designed and synthesized a series of water-soluble prodrugs of the HIV-1 protease inhibitor KNI-727 (1), which is a sparingly water-soluble drug with a water solubility of 5.5 microg/mL. These prodrugs, which contain a water-soluble auxiliary with two tandem-linked units, i.e., a self-cleavable spacer and a solubilizing moiety with an ionized amino function, exhibited a marked increase in water solubility (>10(4)-fold) compared with the parent drug 1. The mechanism of conversion to the parent drug 1 is not enzymatic but through a chemical cleavage at the spacer via an intramolecular cyclization-elimination reaction through an imide formation under physiological conditions. To diversify the conversion time for the parent drug regeneration, chemical modification of the auxiliary was carried out focusing on the introduction of cyclic tertiary amines, which can modify the basicity and/or conformational flexibility of the terminal amino function at the solubilizing moiety, and the change in bond length, which can attenuate the five-membered ring intermediate formation in the cleavage. These newly synthesized water-soluble prodrugs exhibited a practical water solubility with values greater than 50 mg/mL and enabled the constant regeneration of the parent drug 1 with diversified conversion times ranging from 4 min to 34 h as t(1/2) values under physiological conditions. All the water-soluble prodrugs tested regenerated the parent drug 1 in vivo as well as in vitro. A clear increase in the gastrointestinal absorption was observed in prodrugs 8, 12, and 13 with bioavailability (BA) values of 23%, 26%, and 29%, respectively. These BA values were 1.5-1.9-fold higher than that in the administration of the parent drug 1 alone. Other prodrugs showed only a similar or decreased BA compared to the parent drug 1. From these results, we found that not only a high water solubility but also an appropriate conversion time of the prodrug with a relatively narrow limit of around 35 min via intraduodenal administration was necessary for significant improvement of the gastrointestinal absorption in water-soluble prodrugs based on the spontaneous chemical cleavage. This is the first successful water-soluble prodrug that suggests an increased BA value greater than the parent drug in HIV-1 protease inhibitors and is the first study to show the importance of optimal conversion time in water-soluble prodrugs. Consequently, a water-soluble strategy that can control the conversion time would be extensively applicable to improve the gastrointestinal absorption of sparingly water-soluble drugs. The present information is an intriguing discovery and is one of the key factors that will contribute to the future design of practical water-soluble prodrugs.
我们设计并合成了一系列HIV-1蛋白酶抑制剂KNI-727（1）的水溶性前药，KNI-727是一种水溶性较差的药物，其水溶性为5.5微克/毫升。这些前药含有一个带有两个串联单元的水溶性辅助基团，即一个可自裂解的间隔基和一个带有离子化氨基功能的增溶部分，与母体药物1相比，其水溶性显著增加（>10⁴倍）。转化为母体药物1的机制不是酶促反应，而是在生理条件下通过分子内环化消除反应，经酰亚胺形成在间隔基处进行化学裂解。为了使母体药物再生的转化时间多样化，对辅助基团进行了化学修饰，重点是引入环状叔胺，其可改变增溶部分末端氨基功能的碱性和/或构象灵活性，以及改变键长，这可减弱裂解过程中五元环中间体的形成。这些新合成的水溶性前药表现出大于50毫克/毫升的实际水溶性，并能在生理条件下以4分钟至34小时不等的多样化转化时间（t₁/₂值）持续再生母体药物1。所有测试的水溶性前药在体内和体外均能再生母体药物1。在前药8、12和13中观察到胃肠道吸收明显增加，其生物利用度（BA）值分别为23%、26%和29%。这些BA值比单独给予母体药物1时高1.5至1.9倍。与母体药物1相比，其他前药的BA仅显示相似或降低。从这些结果中，我们发现，基于自发化学裂解的水溶性前药要显著改善胃肠道吸收，不仅需要高水溶性，而且前药的转化时间要合适，经十二指肠给药时相对较窄的限制约为35分钟。这是首个成功的水溶性前药，表明在HIV-1蛋白酶抑制剂中其BA值高于母体药物，也是首个表明最佳转化时间在水溶性前药中重要性的研究。因此，一种能够控制转化时间的水溶性策略将广泛适用于改善水溶性差的药物的胃肠道吸收。目前的信息是一个有趣的发现，也是有助于未来设计实用水溶性前药的关键因素之一。
