Small-Sized Human Immunodeficiency Virus Type-1 Protease Inhibitors Containing Allophenylnorstatine to Explore the S2′ Pocket
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- 作者：Koushi Hidaka ; Tooru Kimura ; Hamdy M. Abdel-Rahman ; Jeffrey-Tri Nguyen ; Keith F. McDaniel ; William E. Kohlbrenner ; Akhteruzzaman Molla ; Motoyasu Adachi ; Taro Tamada ; Ryota Kuroki ; Noriko Katsuki ; Yosh
- 刊名：Journal of Medicinal Chemistry
- 出版年：2009
- 出版时间：December 10, 2009
- 年：2009
- 卷：52
- 期：23
- 页码：7604-7617
- 全文大小：1120K
- 年卷期：v.52,no.23(December 10, 2009)
- ISSN：1520-4804
文摘
A series of HIV protease inhibitor based on the allophenylnorstatine structure with various P2′ 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 β-methallyl group at P2′ 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.