Discovery of HIV-1 Protease Inhibitors with Picomolar Affinities Incorporating N-Aryl-oxazolidinone-5-carboxamides as Novel P2 Ligands

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• 作者：Akbar Ali ; G. S. Kiran Kumar Reddy ; Hong Cao ; Saima Ghafoor Anjum ; Madhavi N. L. Nalam ; Celia A. Schiffer ; Tariq M. Rana
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：December 14, 2006
• 年：2006
• 卷：49
• 期：25
• 页码：7342 - 7356
• 全文大小：305K
• 年卷期：v.49,no.25(December 14, 2006)
• ISSN：1520-4804

文摘

Here, we describe the design, synthesis, and biological evaluation of novel HIV-1 protease inhibitorsincorporating N-phenyloxazolidinone-5-carboxamides into the (hydroxyethylamino)sulfonamide scaffold asP2 ligands. Series of inhibitors with variations at the P2 phenyloxazolidinone and the P2' phenylsulfonamidemoieties were synthesized. Compounds with the (S)-enantiomer of substituted phenyloxazolidinones at P2show highly potent inhibitory activities against HIV-1 protease. The inhibitors possessing 3-acetyl, 4-acetyl,and 3-trifluoromethyl groups at the phenyl ring of the oxazolidinone fragment are the most potent in eachseries, with K_i values in the low picomolar (pM) range. The electron-donating groups 4-methoxy and 1,3-dioxolane are preferred at P2' phenyl ring, as compounds with other substitutions show lower binding affinities.Attempts to replace the isobutyl group at P1' with small cyclic moieties caused significant loss of affinitiesin the resulting compounds. Crystal structure analysis of the two most potent inhibitors in complex with theHIV-1 protease provided valuable information on the interactions between the inhibitor and the proteaseenzyme. In both inhibitor-enzyme complexes, the carbonyl group of the oxazolidinone ring makes hydrogenbond interactions with relatively conserved Asp29 residue of the protease. Potent inhibitors from each seriesincorporating various phenyloxazolidinone based P2 ligands were selected and their activities against apanel of multidrug-resistant (MDR) protease variants were determined. Interestingly, the most potent proteaseinhibitor starts out with extremely tight affinity for the wild-type enzyme (K_i = 0.8 pM), and even againstthe MDR variants it retains picomolar to low nanomolar K_i, which is highly comparable with the best FDA-approved protease inhibitors.