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

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 inhib...

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Bibliographic Details
Published in:Journal of medicinal chemistry Vol. 51; no. 18; pp. 5843 - 5855
Main Authors: 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
Format: Journal Article
Language:English
Published: WASHINGTON Amer Chemical Soc 25.09.2008
Subjects:
Administration, Oral
Area Under Curve
Biological Availability
Chemistry, Medicinal
Half-Life
HIV Infections - drug therapy
HIV Integrase Inhibitors - administration & dosage
HIV Integrase Inhibitors - pharmacokinetics
HIV Integrase Inhibitors - pharmacology
HIV Integrase Inhibitors - therapeutic use
Humans
Life Sciences & Biomedicine
Magnetic Resonance Spectroscopy
Mass Spectrometry
Pharmacology & Pharmacy
Pyrrolidinones - administration & dosage
Pyrrolidinones - pharmacokinetics
Pyrrolidinones - pharmacology
Pyrrolidinones - therapeutic use
Raltegravir Potassium
Science & Technology
CELLS
DESIGN
DEPENDENT RNA-POLYMERASE
REPLICATION
4,5-DIHYDROXYPYRIMIDINE
ACIDS
ISSN:0022-2623, 1520-4804, 1520-4804
Online Access:Get more information
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Summary: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.
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ISSN:0022-2623
1520-4804
1520-4804
DOI:10.1021/jm800245z