Design and synthesis of substituted 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides, novel HIV-1 integrase inhibitors

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• 作者：H. Marie Langford ; Peter D. Williams ; Carl F. Homnick ; Joseph P. Vacca ; Peter J. Felock ; Kara A. Stillmock ; Marc V. Witmer ; Daria J. Hazuda ; Lori J. Gabryelski ; William A. Schleif
• 关键词：HIV-1 ; Integrase inhibitor ; Antiviral
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2008
• 出版时间：15 January 2008
• 年：2008
• 卷：18
• 期：2
• 页码：721-725
• 全文大小：140 K

文摘

A series of 4-oxo-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazine-2-carboxamides was synthesized and tested for their inhibition of HIV-1 integrase catalytic activity and HIV-1 replication in cells. Structure–activity studies around lead compound 5 indicated that a coplanar relationship of metal-binding heteroatoms provides optimal binding to the integrase active site. Identification of potency-enhancing substituents and adjustments in lipophilicity provided 17b which inhibits integrase-catalyzed strand transfer with an IC₅₀ value of 74 nM and inhibits HIV-1 replication in cell culture in the presence of 50 % normal human serum with an IC₉₅ value of 63 nM.