Dihydroxypyrimidine-4-carboxamides as Novel Potent and Selective HIV Integrase Inhibitors

Pace, Paola; Francesco, Maria Emilia Di; Gardelli, Cristina; Harper, Steven J.; Muraglia, Ester; Nizi, Emanuela; Orvieto, Federica; Petrocchi, Alessia; Poma, Marco; Rowley, Michael; Scarpelli, Rita; Laufer, Ralph; Paz, Odalys Gonzalez; Monteagudo, Edith; Bonelli, Fabio; Hazuda, Daria J.; Stillmock, Kara A.; Summa, Vincenzo

doi:10.1021/jm070027u

Cited by 70 publications

(65 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1). As with the other RCD compounds, RCD-1 is an abbreviated raltegravir derivative that lacks the oxadiazole substituent, but still shows good activity against HIV-1 IN (IC 50 value ∼60 nM against the strand-transfer reaction of HIV-1 IN) (17). The reduced activity of RCD-1 when compared to raltegravir is attributed to the loss of interactions between the omitted oxadiazole substituent and the surrounding active site residues, specifically Tyr143 of HIV-1 IN or Tyr212 in PFV (13,14,18).…”

Section: Resultsmentioning

confidence: 99%

Probing chelation motifs in HIV integrase inhibitors

Agrawal

DeSoto²,

Fullagar³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

A series of HIV integrase (HIV-1 IN) inhibitors were synthesized to evaluate the role of the metal-binding group (MBG) in this class of metalloenzyme inhibitors. A total of 21 different raltegravirchelator derivative (RCD) compounds were prepared that differed only in the nature of the MBG. These IN strand-transfer inhibitors (INSTIs) were evaluated in vitro in cell-free enzyme activity assays, and the in vitro results were further validated in cell culture experiments. All of the active compounds showed selective inhibition of the strand-transfer reaction over 3′-processing, suggesting a common mode of action with raltegravir. The results of the in vitro activity suggest that the nature of the MBG donor atoms, the overall MBG structure, and the specific arrangement of the MBG donor atom triad are essential for obtaining maximal HIV-1 IN inhibition. At least two compounds (RCD-4, RCD-5) containing a hydroxypyrone MBG were found to display superior strand-transfer inhibition when compared to an abbreviated analogue of raltegravir (RCD-1). By isolating and examining the role of the MBG in a series of INSTIs, we have identified a scaffold (hydroxypyrones) that may provide access to a unique class of HIV-1 IN inhibitors, and may help overcome rising raltegravir resistance.

show abstract

Section: Resultsmentioning

confidence: 99%

Probing chelation motifs in HIV integrase inhibitors

Agrawal

DeSoto²,

Fullagar³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Compound 123 is being studied further for potential clinical development. 64 These results established that introduction of a basic amine group at C-2 in the pyrimidine core improved cell permeability and reduced binding to serum proteins. Interestingly, removing the basic amine in 123 while retaining the tetra-substituted sp 3 carbon (124) did not affect in vitro inhibition (IC 50 5 0.01 mM) and moderately decreased antiviral activity (CIC 95 5 0.25 mM) in the presence of 10% FBS.…”

Section: Dihydroxypyrimidine Carboxamidesmentioning

confidence: 73%

“…Antiviral activity was reduced with an EC 50 value of 5 mM in the presence of 10% FBS and 59 mM in the presence of 50% NHS. 64,65 Several modifications in this scaffold have been explored (Fig. 16).…”

Section: Dihydroxypyrimidine Carboxamidesmentioning

confidence: 99%

HIV-1 integrase inhibitors: 2007-2008 update

et al. 2010

View full text Add to dashboard Cite

In recent years, HIV-1 integrase (IN) has become an attractive target for designing antiretroviral agents. The first IN inhibitor approved for clinical use, raltegravir, has validated the pharmacological viability of IN inhibitors and signals the advent of a new generation of antiretroviral drugs. The development of raltegravir and other successful lead IN inhibitors has also influenced the IN inhibitor design strategy. This has led to the identification of several potent inhibitors in these last two years. Further, an increased understanding of IN structural biology has opened up novel approaches to inhibiting IN, such as targeting its multimerization or interaction with cellular cofactors. This review covers recent developments in the field of IN inhibitor design from 2007 to 2008.

show abstract

“…While many of the protease inhibitors had poor efficacy against SIV, their pharmacokinetics could be assessed in animals, such as that of nelfinavir (Kaldor et al, 1997). Many integrase inhibitors were screened by Merck, leading to testing of many potential new compounds for good bioavailability in nonhuman primates and mice Pace et al, 2007). Even HIV-1 entry inhibitors, such as SCH-D, which would later be named vicriviroc, were tested in mice and monkeys for general pharmacokinetics (Tagat et al, 2004).…”

Section: Toxicity Pharmacokinetics Tissue Distributionmentioning

confidence: 99%

Use of Animal Models for Anti-HIV Drug Development

Ambrose¹

2012

Antiviral Drugs - Aspects of Clinical Use and Recent Advances

View full text Add to dashboard Cite

Dihydroxypyrimidine-4-carboxamides as Novel Potent and Selective HIV Integrase Inhibitors

Cited by 70 publications

References 30 publications

Probing chelation motifs in HIV integrase inhibitors

Probing chelation motifs in HIV integrase inhibitors

HIV-1 integrase inhibitors: 2007-2008 update

Use of Animal Models for Anti-HIV Drug Development

Contact Info

Product

Resources

About