Hamada Yoshio, Ohtake Jun, Sohma Youhei, Kimura Tooru, Hayashi Yoshio, Kiso Yoshiaki
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, Kyoto Pharmaceutical University, Yamashina-Ku, Kyoto, Japan.
Bioorg Med Chem. 2002 Dec;10(12):4155-67. doi: 10.1016/s0968-0896(02)00322-x.
To improve the low water-solubility of HIV protease inhibitors, we synthesized water-soluble prodrugs of KNI-272 and KNI-279 which are potent HIV-1 protease inhibitors consisting of an Apns-Thz core structure (Apns; allophenylnorstatine, Thz; thiazolidine-4-carboxylic acid) as an inhibitory machinery. The prodrugs, which contained an O-acyl peptidomimetic structure with an ionized amino group leading to the increase of water-solubility, were designed to regenerate the corresponding parent drugs based on the O-->N intramolecular acyl migration reaction at the alpha-hydroxy-beta-amino acid residue, that is allophenylnorstatine. The synthetic prodrugs 3, 4, 6, and 7 improved the water-solubility (>300mg/mL) more than 4000-fold in comparison with the parent compounds, which is the practically acceptable value as water-soluble drugs. These prodrugs were stable as an HCl salt and in a strongly acidic solution corresponding to gastric juice (pH 2.0), and could be converted to the parent compounds promptly in the aqueous condition from slightly acidic to basic pH at 37 degrees C, with the suitable migration rate, via a five-membered ring intermediate. Using a similar method, we synthesized a prodrug (12) of ritonavir, a clinically useful HIV-1 protease inhibitor as an anti-AIDS drug. In contrast to the prodrugs 3, 4, 6, and 7, the prodrug 12 was very slowly converted to ritonavir probably through a six-membered ring intermediate, with the t(1/2) value of 32h that may not be suitable for practical use.
为提高HIV蛋白酶抑制剂的低水溶性，我们合成了KNI - 272和KNI - 279的水溶性前药，它们是强效的HIV - 1蛋白酶抑制剂，具有Apns - Thz核心结构（Apns：别苯基去甲亮氨酸，Thz：噻唑烷 - 4 - 羧酸）作为抑制机制。这些前药含有带离子化氨基的O - 酰基拟肽结构，导致水溶性增加，其设计基于α - 羟基 - β - 氨基酸残基（即别苯基去甲亮氨酸）处的O→N分子内酰基迁移反应来再生相应的母体药物。与母体化合物相比，合成的前药3、4、6和7的水溶性提高了4000倍以上（>300mg/mL），这是水溶性药物实际可接受的值。这些前药作为盐酸盐在对应于胃液（pH 2.0）的强酸性溶液中稳定，并且在37℃下从微酸性到碱性pH的水性条件下，可以通过五元环中间体以合适的迁移速率迅速转化为母体化合物。使用类似的方法，我们合成了利托那韦的前药（12），利托那韦是一种临床上有用的抗艾滋病HIV - 1蛋白酶抑制剂。与前药3、4、6和7相比，前药12可能通过六元环中间体非常缓慢地转化为利托那韦，t(½)值为32小时，可能不适合实际使用。
