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

被引：37

作者：

Boros, Eric E. ^{[1
]}

Edwards, Cynthia E. ^{[1
]}

Foster, Scott A. ^{[1
]}

Fuji, Masahiro ^{[2
]}

Fujiwara, Tamio ^{[2
]}

Garvey, Edward P. ^{[1
]}

Golden, Pamela L. ^{[1
]}

Hazen, Richard J. ^{[1
]}

Jeffrey, Jerry L. ^{[1
]}

Johns, Brian A. ^{[1
]}

Kawsuji, Takashi ^{[2
]}

Kiyama, Ryuichi ^{[2
]}

Koble, Cecilia S. ^{[1
]}

Kurose, Noriyuki ^{[2
]}

Miller, Wayne H. ^{[1
]}

Mote, Angela L. ^{[1
]}

Murai, Hitoshi ^{[2
]}

Sato, Akihiko ^{[2
]}

Thompson, James B. ^{[1
]}

Woodward, Mark C. ^{[1
]}

Yoshinaga, Tomokazu ^{[2
]}

机构：

[1] GlaxoSmithKline Res & Dev Ltd, Res Triangle Pk, NC 27709 USA

[2] Shionogi & Co Ltd, Shionogi Res Labs, Fukushima Ku, Osaka 5330002, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 09期

关键词：

INFECTION; MODEL;

D O I：

10.1021/jm801404b

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：2754 / 2761

页数：8

共 26 条

[1] SYNTHESIS OF THE PYRIDINE ANALOGS OF PHTHALIDE [J].

ASHCROFT, WR ;

BEAL, MG ;

JOULE, JA .

JOURNAL OF THE CHEMICAL SOCIETY-PERKIN TRANSACTIONS 1, 1981, (12) :3012-3015

[2] Substituted hepta-1,6-dien-3-ones with green/fruity odours green/galbanum olfactophore model [J].

Bajgrowicz, JA ;

Berg-Schultz, K ;

Brunner, G .

BIOORGANIC & MEDICINAL CHEMISTRY, 2003, 11 (13) :2931-2946

[3]

Billich Andreas, 2003, Curr Opin Investig Drugs, V4, P206

[4] Dipyridyl amides: potent metabotropic glutamate subtype 5 (mGlu5) receptor antagonists [J].

Bonnefous, C ;

Vernier, JM ;

Hutchinson, JH ;

Chung, J ;

Reyes-Manalo, G ;

Kamenecka, T .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2005, 15 (04) :1197-1200

[5] A scaleable synthesis of methyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate [J].

Boros, Eric E. ;

Burova, Svetlana A. ;

Erickson, Greg A. ;

Johns, Brian A. ;

Koble, Cecilia S. ;

Kurose, Noriyuki ;

Sharp, Matthew J. ;

Tabet, Elie A. ;

Thompson, James B. ;

Toczko, Matthew A. .

ORGANIC PROCESS RESEARCH & DEVELOPMENT, 2007, 11 (05) :899-902

[6]

Cabrera C, 2008, CURR OPIN INVEST DR, V9, P885

[7] Modeling, analysis, and validation of a novel HIV integrase structure provide insights into the binding modes of potent integrase inhibitors [J].

Chen, X. ;

Tsiang, M. ;

Yu, F. ;

Hung, M. ;

Jones, G. S. ;

Zeynalzadegan, A. ;

Qi, X. ;

Jin, H. ;

Kim, C. U. ;

Swaminathan, S. ;

Chen, J. M. .

JOURNAL OF MOLECULAR BIOLOGY, 2008, 380 (03) :504-519

[8] PHYSIOLOGICAL-PARAMETERS IN LABORATORY-ANIMALS AND HUMANS [J].

DAVIES, B ;

MORRIS, T .

PHARMACEUTICAL RESEARCH, 1993, 10 (07) :1093-1095

[9]

Egbertson M., 2003, PCT Int. Appl., Patent No. [WO03/062204, 03062204]

[10]

Endo T., 2004, WO, Patent No. [2004/024693, 2004024693]

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