Hidaka Koushi, Kimura Tooru, Abdel-Rahman Hamdy M, Nguyen Jeffrey-Tri, McDaniel Keith F, Kohlbrenner William E, Molla Akhteruzzaman, Adachi Motoyasu, Tamada Taro, Kuroki Ryota, Katsuki Noriko, Tanaka Yoshiaki, Matsumoto Hikaru, Wang Jun, Hayashi Yoshio, Kempf Dale J, Kiso Yoshiaki
Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science, 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.
J Med Chem. 2009 Dec 10;52(23):7604-17. doi: 10.1021/jm9005115.
A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P(2)' moieties were synthesized. Among these analogues, we discovered that a small allyl group would maintain potent enzyme inhibitory activity compared to the o-methylbenzyl moiety in clinical candidate 1 (KNI-764, also known as JE-2147, AG-1776, or SM-319777). Introduction of an anilinic amino group to 2 (KNI-727) improved water-solubility and anti-HIV-1 activity. X-ray crystallographic analysis of 13k (KNI-1689) with a beta-methallyl group at P(2)' position revealed hydrophobic interactions with Ala28, Ile84, and Ile50' similar to that of 1. The presence of an additional methyl group on the allyl group in compound 13k significantly increased anti-HIV activity over 1 while providing a rational drug design for structural minimization and improving membrane permeability.
合成了一系列基于别苯基去甲亮氨酸结构且带有各种P(2)'部分的HIV蛋白酶抑制剂。在这些类似物中，我们发现与临床候选药物1（KNI-764，也称为JE-2147、AG-1776或SM-319777）中的邻甲基苄基部分相比，一个小的烯丙基能保持较强的酶抑制活性。在2（KNI-727）中引入苯胺基氨基改善了水溶性和抗HIV-1活性。对在P(2)'位置带有β-甲基烯丙基的13k（KNI-1689）进行的X射线晶体学分析表明，它与Ala28、Ile84和Ile50'存在与1类似的疏水相互作用。化合物13k中烯丙基上额外甲基的存在显著提高了其相对于1的抗HIV活性，同时为结构最小化和改善膜通透性提供了合理的药物设计。
