Hamada Yoshio, Matsumoto Hikaru, Kimura Tooru, Hayashi Yoshio, Kiso Yoshiaki
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
Bioorg Med Chem Lett. 2003 Aug 18;13(16):2727-30. doi: 10.1016/s0960-894x(03)00576-6.
To improve the low water-solubility of HIV-1 protease inhibitors KNI-272, -279 and -727, we previously reported the water-soluble prodrugs of these inhibitors based on O-->N intramolecular acyl migration reaction. These prodrugs were rapidly converted to the corresponding parent drugs under physiological conditions. To understand the steric and electrostatic effects of O-acyl moiety on the migration rate, we examined several types of prodrug. A remarkably slow migration was observed in the benzoyl-type prodrugs, and Hammett plot of migration rate constants of p-substituted benzoyl-type prodrugs gave a linear free energy relationship.
为提高HIV-1蛋白酶抑制剂KNI-272、-279和-727的低水溶性，我们之前报道了基于O→N分子内酰基迁移反应的这些抑制剂的水溶性前药。这些前药在生理条件下能迅速转化为相应的母体药物。为了解O-酰基部分对迁移速率的空间和静电效应，我们研究了几种类型的前药。在苯甲酰型前药中观察到迁移速度明显较慢，对p-取代苯甲酰型前药迁移速率常数的哈米特图给出了线性自由能关系。
