10-Hydroxy-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d

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• 作者：Catherine M. Wiscount ; Peter D. Williams ; Lekhanh O. Tran ; Mark W. Embrey ; Thorsten E. Fisher ; Vanessa Sherman ; Carl F. Homnick ; D. Donnette Staas ; Terry A. Lyle ; John S. Wai ; Joseph P. Vacca ; ZiQiang
• 关键词：HIV integrase ; Antiviral
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：15 August 2008
• 年：2008
• 卷：18
• 期：16
• 页码：4581-4583
• 全文大小：163 K

文摘

A series of 10-hydroxy-7,8-dihydropyrazino[1′,2′:1,5]pyrrolo[2,3-d]pyridazine-1,9(2H,6H)-diones was synthesized and tested for their inhibition of HIV-1 replication in cell culture. Structure–activity studies indicated that high antiviral potency against wild-type virus as well as viruses containing integrase mutations that confer resistance to three different structural classes of integrase inhibitors could be achieved by incorporation of small aliphatic groups at certain positions on the core template. An optimal compound from this study, 16, inhibits integrase strand-transfer activity with an IC₅₀ value of 10 nM, inhibits HIV-1 replication in cell culture with an IC₉₅ value of 35 nM in the presence of 50 % normal human serum, and displays modest pharmacokinetic properties in rats (iv t_1/2 = 5.3 h, F = 17 % ).