Discovery of Raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection

被引：535

作者：

Summa, Vincenzo ^{[1
]}

Petrocchi, Alessia ^{[1
]}

Bonelli, Fabio ^{[1
]}

Crescenzi, Benedetta ^{[1
]}

Donghi, Monica ^{[1
]}

Ferrara, Marco ^{[1
]}

Fiore, Fabrizio ^{[1
]}

Gardelli, Cristina ^{[1
]}

Paz, Odalys Gonzalez ^{[1
]}

Hazuda, Daria J. ^{[2
]}

Jones, Philip ^{[1
]}

Kinzel, Olaf ^{[1
]}

Laufer, Ralph ^{[1
]}

Monteagudo, Edith ^{[1
]}

Muraglia, Ester ^{[1
]}

Nizi, Emanuela ^{[1
]}

Orvieto, Federica ^{[1
]}

Pace, Paola ^{[1
]}

Pescatore, Giovanna ^{[1
]}

Scarpelli, Rita ^{[1
]}

Stillmock, Kara ^{[2
]}

Witmer, Marc V. ^{[2
]}

Rowley, Michael ^{[1
]}

机构：

[1] SpA Merck Res Labs Rome, Ist Ric Biol Mol P Angeletti, I-00040 Pomezia, Italy

[2] Merck Res Labs, Dept Antiviral Res, West Point, PA USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2008年 / 51卷 / 18期

关键词：

D O I：

10.1021/jm800245z

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.

引用

页码：5843 / 5855

页数：13

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