'Double-drugs' - A new class of prodrug form of an HIV protease inhibitor conjugated with a reverse transcriptase inhibitor by a spontaneously cleavable linker

作     者：Matsumoto, H Hamawaki, T Ota, H Kimura, T Goto, T Sano, K Hayashi, Y Kiso, Y 

作者机构：Kyoto Pharmaceut Univ Ctr Frontier Res Med Sci Dept Med Chem Yamashima Ku Kyoto 6078412 Japan Osaka Med Coll Dept Microbiol Takatsuki Osaka 5698686 Japan 

出 版 物：《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 (生物有机化学与医药化学通讯)

年 卷 期：2000年第10卷第11期

页      面：1227-1231页

核心收录：

学科分类：0710[理学-生物学] 1007[医学-药学(可授医学、理学学位)] 071010[理学-生物化学与分子生物学] 081704[工学-应用化学] 07[理学] 08[工学] 0817[工学-化学工程与技术] 0703[理学-化学] 

基　　金：Japan Health Sciences Foundation, JHSF Ministry of Education, Culture, Sports, Science and Technology, MEXT 

主　　题：抗HIV药/化学 抗HIV药/药理学 HIV蛋白酶抑制药/化学 HIV-1/药物作用 微生物敏感性试验 药物前体/化学 逆转录酶抑制剂/化学 噻唑类/化学 噻唑类/药理学 齐多夫定/类似物和衍生物 齐多夫定/化学 齐多夫定/药理学 人类 

摘      要：We designed and synthesized a new series of prodrug-type anti-HIV agents consisting of a peptidomimetic HIV protease inhibitor conjugated with a nucleoside reverse transcriptase inhibitor in an effort to enhance the antiviral activity. For the conjugation, a series of linkers that conjoin the two different classes of inhibitors have been investigated. Conjugates using a succinyl amino acid linker were shown to release the parent components via the spontaneous imide formation at a faster rate compared to conjugates using a glutaryl amino acid linker, as expected from the energetically favorable cyclization to the five-membered ring. Herein, we report a new double-drug 4b (KNI-1039) with a glutarylglycine linker, which exhibited extremely potent anti-HIV activity compared with that of the individual components. (C) 2000 Elsevier Science Ltd. All rights reserved.