Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1

Corbett, Jeffrey W.; Ko, Soo S.; Rodgers, James D.; Jeffrey, Susan; Bacheler, Lee T.; Klabe, Ronald M.; Diamond, Sharon; Lai, Chii‐Ming; Rabel, Shelley R.; Saye, J; Adams, Stephen P.; Trainor, George L.; Anderson, Paul S.; Erickson‐Viitanen, Susan

doi:10.1128/aac.43.12.2893

Cited by 113 publications

(82 citation statements)

References 10 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In vitro, DPC-083 is active against K103N, K101E and G190S mutations as well as double mutations of K103N-Y181C, K103N-V108I and K103N-P225H, all of which cause significant resistance to EFV (Corbett et al, 2000;Corbett et al, 1999). DPC-083 has an even longer half-life than EFV (>90 h versus 40-45 h), supporting once-daily dosing.…”

Section: Dpc-083mentioning

confidence: 90%

Clinical Utility of Current NNRTIs and Perspectives of New Agents in This Class under Development

Zhang

Hamatake

Hong

2004

Antivir Chem Chemother

View full text Add to dashboard Cite

Highly active antiretroviral therapy (HAART) has significantly reduced the number of deaths caused by AIDS. However, the antiviral efficacy of HAART comprising protease inhibitors (PIs) and nucleoside reverse transcriptase inhibitors (NRTIs) is frequently accompanied by a decrease in patients' quality of life. PI-based therapies often fail due to poor adherence caused by heavy pill burden, complex dosing schedules and undesirable side effects. The current trend is to switch from PI-based to PI-sparing regimens consisting of non-nucleoside reverse transcriptase inhibitors (NNRTIs) and NRTIs. Despite some encouraging results from NNRTI-containing therapies, two major concerns in using the currently available NNRTIs remain: 1) low genetic barrier to the emergence of resistance and 2) cross-resistance due to single mutations that often render the whole class of NNRTIs ineffective. Clearly, new and improved NNRTIs are needed to address these concerns.

show abstract

Section: Dpc-083mentioning

confidence: 90%

Clinical Utility of Current NNRTIs and Perspectives of New Agents in This Class under Development

Zhang

Hamatake

Hong

2004

Antivir Chem Chemother

View full text Add to dashboard Cite

show abstract

“…Three such compounds are presently used clinically, i.e., nevirapine 17, delavirdine 18 and efavirenz 19, whereas two other agents, emivirine 20 and capravirine 21 are in advanced clinical trials and may soon be released for clinical use [1,5,[14][15][16][17][36][37][38][39]. 5, [14][15][16][17][36][37][38][39]. This binding site is situated at about 10 Å from the substrate binding site (where the dNTP and N(t)RTIs bind) being both spatially and functionally associated with it [1,5,[14][15][16][17][36][37][38][39].…”

Section: Non-nucleoside Rtis (Nnrtis)mentioning

confidence: 99%

“…5, [14][15][16][17][36][37][38][39]. This binding site is situated at about 10 Å from the substrate binding site (where the dNTP and N(t)RTIs bind) being both spatially and functionally associated with it [1,5,[14][15][16][17][36][37][38][39].…”

Section: Non-nucleoside Rtis (Nnrtis)mentioning

confidence: 99%

See 1 more Smart Citation

Highly Active Antiretroviral Therapy: Current State of the Art, New Agents and Their Pharmacological Interactions Useful for Improving Therapeutic Outcome

Bárbaro

Scozzafava²,

Mastrolorenzo³

et al. 2005

CPD

211

148

View full text Add to dashboard Cite

Highly active antiretroviral therapy (HAART) dramatically changed the course of HIV infection. Currently, this therapy involves the use of agents from at least two distinct classes of antivirals: a protease inhibitor (PI) in combination with two nucleoside/nucleotide reverse transcriptase inhibitors (N(t)RTIs), or a non-nucleoside reverse transcriptase inhibitor (NNRTI) in combination with NRTIs. Recently, the third family of antivirals started to be used clinically, with the advent of enfuvirtide, the first fusion inhibitor (FI). Several pharmacological agents are available form these classes of antivirals, NRTIs, NNRTIs, PIs and FIs, which will be briefly reviewed here. Some more agents are in advanced clinical evaluation or have recently been approved (such as tenofovir, a NtRTI; atazanavir, a PI; tipranavir, another PI), mainly against drug-resistant viruses. Compounds inhibiting HIV integrase, the third enzyme of HIV, are also available ultimately, with several such derivatives in clinical trials (L-731, 988 and S-1360). Another approach to inhibit the growth of retroviruses, including HIV, targets the ejection of zinc ions from critical zinc finger viral proteins, which has as a consequence the inhibition of viral replication in the absence of mutations leading to drug resistance phenotypes. All steps in the process of HIV entry into the cell may be targeted by specific compounds that might be developed as novel types of antiretrovirals. Thus, inhibitors of the gp120-CD4 interaction have been detected (zintevir, FP-21399 and BMS-378806 in clinical trials). Small molecule chemokine antagonists acting as HIV entry inhibitors also were described in the last period, which interact both with the CXCR4 coreceptor (such as AMD3100; AMD3465; ALX40-4C; T22, T134 and T140), or which are antagonist of the CCR5 coreceptor (TAK-779, TAK-220, SCH-C, SCH-D, E913, AK-602 and NSC 651016 in clinical trials), together with new types of fusion inhibitors possessing the same mechanism of action as enfuvirtide (such as T1249). Compounds interacting with Tat/Tar have also been detected which inhibit HIV replication in low micromolar range (EM2487, tamacrazine, CGP 64222 or CGA 137053 among others). Unexploited viral and cellular targets (such as the maturation process-with a first potent compound available, PA-457; the cellular proteins Tsg101, APOBEC3G, or the viral ones Vif, Rev or RNase H) are also presented, together with recently emerged approaches for eradication of HIV reservoirs. A review on the pharmacology and interactions of these agents with other drugs is presented here, with emphasis on how these pharmacological interferences may improve the clinical use of antivirals, or how side effects due to these drugs may be managed better by taking them into account.

show abstract

“…Introduction of a trifluoromethyl group into molecules of organic compounds endows them with qualitatively new chemical and biological properties [14,15]; of particular interest are structures in which trifluoromethyl group is attached to an asymmetric carbon atom [16,17]. We previously synthesized optically active 4-aryl-4-trifluoromethyl-3,4-dihydropyrimidine-2(1H)-thiones having no substituent on N 1 by condensation of chiral β-trifluoromethyl-β-amino ketones with potassium thiocyanate or acyl isothiocyanates [18].…”

mentioning

confidence: 99%

Synthesis of (S)-(-)-1,4-diaryl-6-methyl-4-trifluoromethyl-3,4-dihydropyrimidine-2(1H)-thiones

2012

View full text Add to dashboard Cite

show abstract

Expanded-Spectrum Nonnucleoside Reverse Transcriptase Inhibitors Inhibit Clinically Relevant Mutant Variants of Human Immunodeficiency Virus Type 1

Cited by 113 publications

References 10 publications

Clinical Utility of Current NNRTIs and Perspectives of New Agents in This Class under Development

Clinical Utility of Current NNRTIs and Perspectives of New Agents in This Class under Development

Highly Active Antiretroviral Therapy: Current State of the Art, New Agents and Their Pharmacological Interactions Useful for Improving Therapeutic Outcome

Synthesis of (S)-(-)-1,4-diaryl-6-methyl-4-trifluoromethyl-3,4-dihydropyrimidine-2(1H)-thiones

Contact Info

Product

Resources

About