- Hydroxyl may not be indispensable for raltegravir: Design, synthesis and SAR Studies of raltegravir derivatives as HIV-1 inhibitors
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A series of raltegravir derivatives 20-42 were prepared and systematically evaluated for their anti-HIV activity. The bioassay results showed that most of the compounds possess good to excellent anti-HIV activity. Especially, compounds 25 and 35 with subpicomole IC50 values seemed to be the most potent anti-HIV agents among all of the reported synthesized compounds. These compounds may therefore be considered as new potent anti-HIV agents. The 5-hydroxyl modification of raltegravir derivatives significantly increased the anti-HIV activity, which indicates that the hydroxyl may not be indispensable for raltegravir. The introducing of acyl at 5-position of raltegravir derivatives is favorable for antiviral activity. In addition, a high-throughput cell-based assay method with pseudotyped virus stocks was developed and used to identify HIV inhibitors.
- Wang, Ziwen,Wang, Mingxiao,Yao, Xue,Li, Yue,Qiao, Wentao,Geng, Yunqi,Liu, Yuxiu,Wang, Qingmin
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p. 361 - 369
(2012/06/30)
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- Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection
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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.
- Summa, Vincenzo,Petrocchi, Alessia,Bonelli, Fabio,Crescenzi, Benedetta,Donghi, Monica,Ferrara, Marco,Fiore, Fabrizio,Gardelli, Cristina,Paz, Odalys Gonzalez,Hazuda, Daria J.,Jones, Philip,Kinzel, Olaf,Laufer, Ralph,Monteagudo, Edith,Muraglia, Ester,Nizi, Emanuela,Orvieto, Federica,Pace, Paola,Pescatore, Giovanna,Scarpelli, Rita,Stillmock, Kara,Witmer, Marc V.,Rowley, Michael
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experimental part
p. 5843 - 5855
(2009/09/25)
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