双取代双四氢呋喃基团作为非肽类HIV-1蛋白酶抑制剂中的新型P2配体
Disubstituted Bis-THF Moieties as New P2 Ligands in Nonpeptidal HIV-1 Protease Inhibitors.
作者信息
Hohlfeld Konrad, Tomassi Cyrille, Wegner Jörg Kurt, Kesteleyn Bart, Linclau Bruno
机构信息
School of Chemistry, University of Southampton , Highfield, Southampton SO17 1BJ, United Kingdom.
Tibotec , Turnhoutseweg 30, 2340 Beerse, Belgium.
出版信息
ACS Med Chem Lett. 2011 Mar 31;2(6):461-5. doi: 10.1021/ml2000356. eCollection 2011 Jun 9.
Abstract
A series of darunavir analogues featuring a substituted bis-THF ring as P2 ligand have been synthesized and evaluated. High affinity protease inhibitors (PIs) with an interesting activity on wild-type HIV and a panel of multi-PI resistant HIV-1 mutants containing clinically observed, primary mutations were identified using a cell-based assay. A number of PIs have been synthesized that show equivalent and greater activity for HIV-1 mutant strains as compared to wild-type HIV-1. The activity on the purified enzyme was confirmed for a selection of analogues.
摘要
已合成并评估了一系列以取代双四氢呋喃环作为P2配体的地瑞那韦类似物。使用基于细胞的测定法鉴定了对野生型HIV具有有趣活性的高亲和力蛋白酶抑制剂（PIs），以及一组包含临床观察到的原发性突变的多PI耐药HIV-1突变体。已合成了许多对HIV-1突变株显示出与野生型HIV-1相当或更高活性的PIs。对选定的类似物进行了纯化酶活性的确认。
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