Raltegravir: The first HIV integrase inhibitor

Cocohoba, Jennifer; Dong, Betty J.

doi:10.1016/j.clinthera.2008.10.012

Cited by 102 publications

(73 citation statements)

References 19 publications

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“…Raltegravir is the first agent in a new class of antiretrovirals, HIV integrase inhibitors. It has a demonstrated potent efficacy against multidrug-resistant HIV-1 and was initially approved by Food and Drug Administration in 2007 to treat treatment-experienced HIV-1-infected patients (Cocohoba and Dong, 2008;Steigbigel et al, 2008;Elbasha et al, 2009;Hughes et al, 2009). Based on the most recent guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents released by the United States Department of Health and Human Services in December 2009, raltegravir also has been listed as one of the preferred regimens recommended for treatment-naive HIV-1-infected patients.…”

Section: Discussionmentioning

confidence: 99%

“…Raltegravir (also known as MK0518, Isentress) is a first-in-its-class oral integrase inhibitor and was approved by the Food and Drug Administration on October 12, 2007 (Nair andChi, 2007;Cocohoba and Dong, 2008). Raltegravir prevents the integration of proviral DNA into host genome and has potent in vitro inhibitory activity against HIV-1 strains that are resistant to other antiretroviral regimens (Cocohoba and Dong, 2008). Limited clinical studies have shown that raltegravir has equal or greater therapeutic efficacy in treatment of both naive and experienced patients Steigbigel et al, 2008;Imaz et al, 2009).…”

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confidence: 99%

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Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

Cao¹,

Hu²,

Wang³

et al. 2010

J Pharmacol Exp Ther

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Hyperlipidemia associated with the HIV protease inhibitor (PI), the major component of highly active antiretroviral treatment (HAART) for HIV infection, has stimulated interest in developing new agents that minimize these side effects in the clinic. HIV integrase inhibitor is a new class of anti-HIV agents. Raltegravir is a first-in-its-class oral integrase inhibitor and has potent inhibitory activity against HIV-1 strains that are resistant to other antiretroviral regimens. Our previous studies have demonstrated that HIV PI-induced endoplasmic reticulum (ER) stress links to dysregulation of lipid metabolism. However, little information is available as to whether raltegravir would have similar effects as the HIV PIs. In this study, we examined the effect of raltegravir on lipid metabolism both in primary rat hepatocytes and in in vivo mouse models, and we further determined whether the combination of raltegravir with existing HIV PIs would potentially exacerbate or prevent the previously observed development of dyslipidemia. The results indicated that raltegravir did not induce ER stress or disrupt lipid metabolism either in vitro or in vivo. However, HIV PI-induced ER stress and lipid accumulation were significantly inhibited by raltegravir both in in vitro primary rat hepatocytes and in in vivo mouse liver. High-performance liquid chromatography analysis further demonstrated that raltegravir did not affect the uptake and metabolism of HIV PIs in hepatocytes. Thus, raltegravir has less hepatic toxicity and could prevent HIV PI-induced dysregulation of lipid metabolism by inhibiting ER stress. These results suggest that incorporation of this HIV integrase inhibitor may reduce the side effects associated with current HAART.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

Cao¹,

Hu²,

Wang³

et al. 2010

J Pharmacol Exp Ther

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“…It inhibits the action of the HIV-1-specific enzyme that is responsible for the insertion of viral complimentary DNA into the host genome (Croxtall & Keam, 2009). It is also found to be a generally well tolerated antiretroviral agent that may play an important role in the treatment of patients harboring resistance to other antiretroviral drugs (Cocohoba & Dong, 2008). A review of the pharmacokinetics, pharmacology and clinical studies of Raltegravir has been published (Burger, 2010).…”

Section: Methodsmentioning

confidence: 99%

“…For general background to and pharmacological properties of Raltegravir, see: Burger (2010); Cocohoba & Dong (2008); Croxtall & Keam (2009) ;Evering & Markowitz (2008); Hicks & Gulick (2009);Savarino (2006); Temesgen & Siraj (2008). For related structures, see : Fun et al (2011);Shang et al (2012) ;Shang, Qi et al (2011);Thiruvalluvar et al (2007).…”

Section: Related Literaturementioning

confidence: 99%

Raltegravir monohydrate

et al. 2013

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The hydrated title compound [systematic name: N-(4-fluorobenzyl)-5-hydroxy-1-methyl-2-{1-methyl-1-[(5-methyl-1,3,4-oxadiazol-2-ylcarbonyl)amino]ethyl}-6-oxo-1,6-dihydropyrimidine-4-carboxamide monohydrate], C20H21FN6O5·H2O, is recognised as the first HIV integrase inhibitor. In the molecule, the dihedral angles between the mean planes of the pyrimidine ring and the phenyl and oxadiazole rings are 72.0 (1) and 61.8 (3)°, respectively. The mean plane of the oxadiazole ring is twisted by 15.6 (3)° from that of the benzene ring, while the mean plane of amide group bound to the oxadiaole ring is twisted by 18.8 (3)° from its mean plane. Intramolecular O—H...O and C—H...N hydrogen bonds are observed in the molecule. The crystal packing features O—H...O hydrogen bonds, which include bifurcated O—H...(O,O) hydrogen bonds from one H atom of the water molecule. In addition, N—H...O hydrogen bonds are observed involving the two amide groups. These interactions link the molecules into chains along [010]

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“…No functional equivalent for HIV-1 integrase has been found in human cells, suggesting that the integrase enzyme is one of the best candidates for designing and developing new inhibitors/drugs for HIV/AIDS treatment. 2,3 Hence, integrase is a signi¯cant target for chemotherapy and development of therapeutic anti-HIV-1 agents. 4 There are a number of diverse classes of compounds that inhibit integrase activity in vitro.…”

Section: Introductionmentioning

confidence: 99%

Quantitative structure–activity relationships study of potent pyridinone scaffold derivatives as HIV-1 integrase inhibitors with therapeutic applications

Barzegar

Hamidi

2017

J. Theor. Comput. Chem.

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Human immunode¯ciency virus-1 (HIV-1) integrase appears to be a crucial target for developing new anti-HIV-1 therapeutic agents. Di®erent quantitative structure-activity relationships (QSARs) algorithms have been used in order to develop e±cient model(s) to predict the activity of new pyridinone derivatives against HIV-1 integrase. Multiple linear regression (MLR) and combined principal component analysis (PCA) with MLR have been applied to build QSAR models for a set of new pyridinone derivatives as potent anti-HIV-1 therapeutic agents. Four di®erent approaches based on MLR method including; concrete-MLR, stepwise-MLR, concrete PCA-MLR and stepwise PCA-MLR were utilized for this aim. Twenty two di®erent sets of descriptors containing 1613 descriptors were constructed for each optimized molecule. Comparison between predictability of the \concrete" and \stepwise" procedure in two di®erent algorithms of MLR and PCA models indicated the advantage of the stepwise procedure over that of the simple concrete method. Although the PCA was employed for dimension reduction, using stepwise PCA-MLR model showed that the method has higher ability to predict the compounds' activity. The stepwise PCA-MLR model showed highly validated statistical results both in¯tting and prediction processes (R 2 test ¼ 0:78 and Q 2 ¼ 0:80). Therefore, using stepwise PCA approach is suitable to remove ine®ective descriptors, which results in remaining e±cient descriptors for building good predictability stepwise PCA-MLR. The stepwise hybrid approach of PCA-MLR may be useful in derivation of highly predictive and interpretable QSAR models.

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Raltegravir: The first HIV integrase inhibitor

Cited by 102 publications

References 19 publications

Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

Prevention of HIV Protease Inhibitor-Induced Dysregulation of Hepatic Lipid Metabolism by Raltegravir via Endoplasmic Reticulum Stress Signaling Pathways

Raltegravir monohydrate

Quantitative structure–activity relationships study of potent pyridinone scaffold derivatives as HIV-1 integrase inhibitors with therapeutic applications

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