Synthesis and Antiviral Activity of 7-Benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV Integrase Inhibitors

详细信息    查看全文

• 作者：Eric E. Boros ; Cynthia E. Edwards ; Scott A. Foster ; Masahiro Fuji ; Tamio Fujiwara ; Edward P. Garvey ; Pamela L. Golden ; Richard J. Hazen ; Jerry L. Jeffrey ; Brian A. Johns ; Takashi Kawasuji ; Ryuichi Kiy
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：May 14, 2009
• 年：2009
• 卷：52
• 期：9
• 页码：2754-2761
• 全文大小：189K
• 年卷期：v.52,no.9(May 14, 2009)
• ISSN：1520-4804

文摘

The medicinal chemistry and structure−activity relationships for a novel series of 7-benzyl-4-hydroxy-1,5-naphthyridin-2(1H)-one HIV-integrase inhibitors are disclosed. Substituent effects were evaluated at the N-1, C-3, and 7-benzyl positions of the naphthyridinone ring system. Low nanomolar IC₅₀ values were achieved in an HIV-integrase strand transfer assay with both carboxylic ester and carboxamide groups at C-3. More importantly, several carboxamide congeners showed potent antiviral activity in cellular assays. A 7-benzyl substituent was found to be critical for potent enzyme inhibition, and an N-(2-methoxyethyl)carboxamide moiety at C-3 significantly reduced plasma protein binding effects in vitro. Pharmacokinetic data in rats for one carboxamide analogue demonstrated oral bioavailability and reasonable in vivo clearance.