HIV-1蛋白酶抑制剂KNI-727的水溶性前药的开发：转化时间对基于自发化学裂解的前药更高胃肠道吸收的重要性。,Journal of Medicinal Chemistry

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HIV-1蛋白酶抑制剂KNI-727的水溶性前药的开发：转化时间对基于自发化学裂解的前药更高胃肠道吸收的重要性。
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2003 Sep 11 , DOI: 10.1021/jm030009m
Youhei Sohma ₁ , Yoshio Hayashi ₁ , Tomoko Ito ₁ , Hikaru Matsumoto ₁ , Tooru Kimura ₁ , Yoshiaki Kiso ₁

Affiliation

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，这是一种微水溶性药物，水溶性为5.5 microg / mL。这些前药包含具有两个串联连接单元的水溶性助剂，即自裂解间隔基和具有离子化氨基功能的增溶部分，它们的水溶性显着提高（> 10（4）倍）与母体药物1相比，转化为母体药物1的机制不是酶促的，而是通过在生理条件下通过酰亚胺形成的分子内环化消除反应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，辅助剂的化学修饰主要集中在环状叔胺的引入上，它可以修饰可溶部分的末端氨基官能团的碱性和/或构象柔性，以及键长的变化，从而可以减弱五-在裂解中形成一元环中间。这些新合成的水溶性前药显示出实用的水溶性，其值大于50 mg / mL，并且能够以4（t）/ min（t）/（t）/（t）/（t）/（t / 1/2））的范围内的多种转化时间持续稳定地再生母体药物1生理条件。所有测试的水溶性前药均在体内和体外再生了母体药物1。在前药8、12中观察到胃肠道吸收明显增加。和13的生物利用度（BA）值分别为23％，26％和29％。这些BA值比单独施用母体药物1时高1.5-1.9倍。与前药1相比，其他前药仅显示相似或降低的BA。从这些结果中，我们发现通过十二指肠内给药，不仅前药具有较高的水溶性，而且具有适当的转化时间，且相对狭窄的限度约为35分钟对于基于自发化学裂解的水溶性前药，其对胃肠道吸收的显着改善是必需的。这是第一个成功的水溶性前药，表明在HIV-1蛋白酶抑制剂中BA值的增加大于母体药物的BA值，并且是第一个显示水溶性前药中最佳转化时间的重要性的研究。因此，可以控制转化时间的水溶性策略将广泛适用于改善少量水溶性药物的胃肠道吸收。目前的信息是一个有趣的发现，并且是有助于实用的水溶性前药未来设计的关键因素之一。

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Development of water-soluble prodrugs of the HIV-1 protease inhibitor KNI-727: importance of the conversion time for higher gastrointestinal absorption of prodrugs based on spontaneous chemical cleavage.

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.

更新日期：2017-01-31

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