Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Reverse Transcriptase Inhibitors”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 703 records · Page 39Linked to original sources
PubMed2001

Synthesis and evaluation of efavirenz (Sustiva) analogues as HIV-1 reverse transcriptase inhibitors: replacement of the cyclopropylacetylene side chain.

Two series of efavirenz analogues have been developed: one in which the cyclopropane ring has been replaced by small heterocycles and another in which the entire acetylenic side chain has been replaced by alkyloxy groups. Several members of both series show equivalent potency to efavirenz against both wild-type virus and the key K103N mutant.

Alkynes↗
PubMed2005

Changes in renal function associated with tenofovir disoproxil fumarate treatment, compared with nucleoside reverse-transcriptase inhibitor treatment.

In our large observational cohort, use of tenofovir disoproxil fumarate (n=344) was associated with a greater decline in renal function than was use of alternative nucleoside analogues (n=314). Other associations included a lower CD4 cell count, decreased renal function at baseline, and diabetes. The declines were modest and did not lead to greater rates of discontinuation of therapy.

Adenine↗
PubMed2004

Nonnucleoside HIV-1 reverse transcriptase inhibitors; part 3. Synthesis and antiviral activity of 5-alkyl-2-[(aryl and alkyloxyl-carbonylmethyl)thio]-6-(1-naphthylmethyl) pyrimidin-4(3H)-ones.

A series of 6-naphthylmethyl substituted S-alkylated dihydroalkoxybenzyloxopyrimidine (S-DABO) analogues with a beta-carbonyl group on the C-2 side chain were synthesized. All of the new compounds were evaluated for their anti-HIV activities in MT-4 cells. The most active compound, 5-isopropyl-2-[(4'-methoxyphenylcarbonyl-methyl)thio]-6-(1-naphthylmethyl)pyrimidin-4(3H)-one showed activity against HIV-1 and against the double mutated strain of HIV(Y181C and K103N) in the micromolar range. Furthermore, some of the compounds are active against both HIV-1 and HIV-2 in cell culture. In view of the fact that the loss of antiviral activity of these compounds when tested against S0561945 was much less pronounced than the loss of activity of typical NNRTIs, it is concluded that some of the compounds might interfere with another target or act on reverse transcriptase in a different way than the typical NNRTIs.

Anti-HIV Agents↗
PubMed2004

Synthesis of 5-alkynylated d4T analogues as potential HIV-1 reverse transcriptase inhibitors.

A series of 2',3'-didehydro-2',3'-dideoxynucleosides substituted with an alkynylhydroxy- (6, 7, 12 and 13) and alkynylamino- (20) groups at the C-5 position were synthesized. All these five target modified nucleosides were tested for anti-human immunodeficiency virus type 1 activity in CEM-SS and MT-4 cells and unfortunately displayed no improvement in antiviral activity.

Alkynes↗
PubMed1998

Synthesis and anti-HIV activities of urea-PETT analogs belonging to a new class of potent non-nucleoside HIV-1 reverse transcriptase inhibitors.

A series of potent specific HIV-1 RT inhibitory compounds is described. The compounds are urea analogs of PETT (PhenylEthylThiazoleThiourea) derivatives and the series includes derivatives with an ethyl linker (1-6) and conformationally restricted analogs (7-13). The antiviral activity is determined both at the RT level and in cell culture on both native and mutant forms of HIV-1. Many compounds display activity in the nM range against wt-RT.

Anti-HIV Agents↗
PubMed2000

An efficient chiral moderator prepared from inexpensive (+)-3-carene: synthesis of the HIV-1 non-nucleoside reverse transcriptase inhibitor DPC 963.

The beta-amino alcohol 4 beta-morpholinocaran-3 alpha-ol is prepared by addition of morpholine to alpha-3,4-epoxycarane utilizing anhydrous magnesium bromide as Lewis acid promoter. The enantiopure amino alcohol is uniquely effective as a chiral moderator for the addition of lithium cyclopropylacetylide to an unprotected N-acylketimine. This reaction provides an efficient route to the second generation NNRTI drug candidate DPC 963.

HIV-1↗
PubMed2006

Synthesis and anti-HIV activity evaluation of 1-[(alkenyl or alkynyl or alkyloxy)methyl]-5-alkyl-6-(1-naphthoyl)-2,4-pyrimidinediones as novel non-nucleoside HIV-1 reverse transcriptase inhibitors.

The synthesis and anti-HIV activity evaluation of a new series of 2,4-pyrimidinediones bearing a 6-(1-naphthoyl) group are described. In general, it was found that most of the title compounds showed good activities against human immunodeficiency virus type-1 (HIV-1). In particular, compound 26 displayed the most potent anti-HIV-1 activity (IC(50)=0.11+/-0.05 microM), inhibiting HIV-1 replication in MT-4 cells more effectively than HEPT (by 45-fold) and DDI (by 50-fold).

Alkenes↗
PubMed2006

Arylthiopyrrole (AThP) derivatives as non-nucleoside HIV-1 reverse transcriptase inhibitors: synthesis, structure-activity relationships, and docking studies (part 1).

Novel arylthio isopropyl pyridinylmethylpyrrolemethanol (AThP) derivatives 3-5, which are related to capravirine (S-1153), were synthesized and tested for their ability to block the replication cycle of HIV-1 in infected cells. The newly synthesized AThPs are active in the concentration range of 0.008-53 microM. Even if compounds 3-5 are generally less potent than S-1153, their SI values are in some cases similar to that of the reference drug. In fact, the cytotoxicities of AThPs are generally lower than that of S-1153. Compound 4e was the most active derivative of this series in cell-based assays; its potency is similar to that of S-1153 (EC(50)=8 and 3 nM, respectively), as is its selectivity index (SI=6250 and 7000, respectively). AThP derivatives were proven to target HIV-1 RT. In fact, compounds 3-5 generally inhibited the viral enzyme at concentrations similar to those observed in cell-based assays. A selected number of AThPs (4k and 5a,e) were tested against clinically relevant drug-resistant forms of recombinant reverse transcriptase (rRT) carrying the K103N and Y181I mutations. Carbamate 5e showed an approximate 240-fold decrease in activity against Y181I, but only a 10-fold loss in potency against the K103N rRT form. Docking calculations were also performed to investigate the binding mode of compounds 2, 4e, 4j, 4k and 5e into the non-nucleoside binding site of HIV-1 RT and to rationalize some structure-activity relationships and resistance data.

Binding Sites↗
PubMed2001

Resistance to nucleoside analog reverse transcriptase inhibitors mediated by human immunodeficiency virus type 1 p6 protein.

Resistance of human immunodeficiency virus type 1 (HIV-1) to antiretroviral agents results from target gene mutation within the pol gene, which encodes the viral protease, reverse transcriptase (RT), and integrase. We speculated that mutations in genes other that the drug target could lead to drug resistance. For this purpose, the p1-p6(gag)-p6(pol) region of HIV-1, placed immediately upstream of pol, was analyzed. This region has the potential to alter Pol through frameshift regulation (p1), through improved packaging of viral enzymes (p6(Gag)), or by changes in activation of the viral protease (p6(Pol)). Duplication of the proline-rich p6(Gag) PTAP motif, necessary for late viral cycle activities, was identified in plasma virus from 47 of 222 (21.2%) patients treated with nucleoside analog RT inhibitor (NRTI) antiretroviral therapy but was identified very rarely from drug-naïve individuals. Molecular clones carrying a 3-amino-acid duplication, APPAPP (transframe duplication SPTSPT in p6(Pol)), displayed a delay in protein maturation; however, they packaged a 34% excess of RT and exhibited a marked competitive growth advantage in the presence of NRTIs. This phenotype is reminiscent of the inoculum effect described in bacteriology, where a larger input, or a greater infectivity of an organism with a wild-type antimicrobial target, leads to escape from drug pressure and a higher MIC in vitro. Though the mechanism by which the PTAP region participates in viral maturation is not known, duplication of this proline-rich motif could improve assembly and packaging at membrane locations, resulting in the observed phenotype of increased infectivity and drug resistance.

Amino Acid Sequence↗
PubMed2004

5-Alkyl-2-[(aryl and alkyloxylcarbonylmethyl)thio]-6-(1-naphthylmethyl) pyrimidin-4(3H)-ones as an unique HIV reverse transcriptase inhibitors of S-DABO series.

The introduction of a beta-carbonyl group to the C-2 side chain of S-DABO led to the finding of a series of novel potent anti-HIV agent. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations. Furthermore, the novel S-DABOs differ from the classical NNRTIs in that some compounds are active against both HIV-1 and HIV-2. They might interfere with another target or at least act on RT in a different way as compared to typical NNRTIs.

Anti-HIV Agents↗
PubMed2004

Severe lactic acidosis in association with reverse transcriptase inhibitors with potential response to L-carnitine in a pediatric HIV-positive patient.

We report a case of life-threatening lactic acidosis in a 10-year-old male with HIV stage B2 infection, presumed to be vertically acquired. This occurred after several months of therapy with d4t, ddl, and nevirapine. His most recent CD4 count was 347 cells per microliter and viral load 16,000 copies per milliliter 3 weeks prior to admission. The peak lactic acid level was 12.4 mmol/L. Although multiple therapeutic interventions took place, the patient showed rapid improvement and resolution temporally associated with the administration of levocarnitine.

Acidosis, Lactic↗
PubMed2004

Artificial neural networks: non-linear QSAR studies of HEPT derivatives as HIV-1 reverse transcriptase inhibitors.

Structure-anti HIV activity relationships were established for a sample of 80 1-[2-hydroxyethoxy-methyl]-6-(phenylthio)thymine (HEPT) using a three-layer neural network (NN). Eight structural descriptors and physicochemical variables were used to characterize the HEPT derivatives under study. The network's architecture and parameters were optimized in order to obtain good results. All the NN architectures were able to establish a satisfactory relationship between the molecular descriptors and the anti-HIV activity. NN proved to give better results than other models in the literature. NN have been shown to be particularly successful in their ability to identify non-linear relationships.

Anti-HIV Agents↗
PubMed1998

A novel mutation (F227L) arises in the reverse transcriptase of human immunodeficiency virus type 1 on dose-escalating treatment of HIV type 1-infected cell cultures with the nonnucleoside reverse transcriptase inhibitor thiocarboxanilide UC-781.

Treatment of wild-type human immunodeficiency virus [HIV-1(IIIB)]-infected cell cultures with the thiocarboxanilide UC-781 under low selective pressure (i.e., 0.01 microg/ml) resulted in the emergence of V106A RT mutant virus. On increasing drug concentrations (stepwise up to 30 microg/ml) the virus retained the V106A RT mutation but acquired the novel F227L mutation in the RT genome in addition to the L100I, K1O1I, and Y181C mutations. This multiple-mutant virus proved highly resistant to virtually all nonnucleoside RT inhibitors (NNRTIs) (e.g., nevirapine, delavirdine, and loviride), but retained full sensitivity to nucleoside analogs such as AZT, ddI, (-)FTC, and 3TC. The F227 amino acid is highly conserved in HIV-1 strains and forms part of the NNRTI-binding pocket. Our model suggests a hydrophobic interaction between F227 and the chloro atom of UC-781.

Anilides↗
PubMed2005

Pharmacokinetics of nelfinavir and efavirenz in antiretroviral-naive, human immunodeficiency virus-infected subjects when administered alone or in combination with nucleoside analog reverse transcriptase inhibitors.

Pharmacokinetic studies were conducted with human immunodeficiency virus-infected patients receiving efavirenz, nelfinavir, or both agents at weeks 4 and 32. Reductions of 25% and 45% were observed in the mean nelfinavir area under the concentration-time curve and minimum concentration of the drug in serum, and there was a 31% more rapid half-life for patients receiving both drugs compared to patients receiving nelfinavir alone. There were no significant differences in efavirenz pharmacokinetics.

Alkynes↗
PubMed2005

Effect of first line therapy including efavirenz and two nucleoside reverse transcriptase inhibitors in HIV-infected children.

OBJECTIVE: In an intent-to-treat study, reduction of viral load, increase in CD4 cell count, clinical benefit and adverse reactions were examined in HIV-infected children receiving first line therapy including efavirenz. METHODS: The data of 10 perinatally infected children (median age: 5.8 years) were evaluated during a treatment period of 24 months. Viral load and CD4 cell count were measured every 4 - 8 weeks. Pharmacokinetic evaluations of efavirenz were performed in all patients at study onset. Adverse reactions were reported after obtaining interval history and examination. RESULTS: At base line, median CD4 cell count was 378 cells/microl (21%) and median viral load was 350,000 copies/ml (5.5 log10 copies/ml). After 24 months of treatment, the median viral load reduction was > 3.5 log10 copies/ ml and HIV-1 RNA < 50 copies/ml was found in 8/10 children (80%). Median CD4 cell count increased to 721 cells/microl (24%) after 3 months and was maintained at a level of >1000 cells/microl (> 25%) after 24 months of treatment. Regarding efavirenz levels, C min. values ranged from 845 to 3550 ng/ml (median: 1845 ng/ml) and C max. values from 2380 to 24 200 ng/ ml (median: 3670 ng/ml). The most common adverse effect was a mild skin rash (4/10 children). CNS symptoms were recorded in one patient and no hyperlipidaemia was seen. CONCLUSION: First line therapy with efavirenz and two NRTIs was well tolerated by HIV-1 infected children and the reduction of viral load seems to be similar to single protease inhibitor-containing regimens.

Administration, Oral↗
PubMed2001

High-performance liquid chromatographic method for the determination of HIV-1 non-nucleoside reverse transcriptase inhibitor efavirenz in plasma of patients during highly active antiretroviral therapy.

A new high-performance liquid chromatographic method for the determination of efavirenz in human plasma is described. Quantitative recovery following liquid-liquid extraction with diethylether from 200 microl of human plasma was achieved. Subsequently, the assay was performed with 67 mM potassium dihydrogen phosphate-acetonitrile as a mobile phase, a XTerraRP 18 column protected with a Phenomenex C18 column and UV detection at 246 nm. Linear standard curves were obtained for concentrations ranging from 25 to 15,000 ng/ml. The calculated intra- and inter-day coefficients of variation were below 10%.

Alkynes↗
PubMed2005

Resistance to nonnucleoside reverse-transcriptase inhibitors and prevalence of HIV type 1 non-B subtypes are increasing among persons with recent infection in Spain.

The prevalence of drug resistance mutations was 12.1% among 198 persons who experienced human immunodeficiency virus (HIV) seroconversion identified in Spain during 1997-2004. There was a significant increase of K103N and of non-B subtypes over time. Transmission of HIV infection around the time of seroconversion was shown in 8 couples and in 2 clusters of 3 individuals.

Adult↗
PubMed2003

Nonnucleoside reverse transcriptase inhibitor resistance among antiretroviral-naive HIV-positive pregnant women.

From 1999 to 2001, the overall prevalence of resistance in the antiretroviral (ART)-naive population in St. Louis, Missouri, was 17%. We sought to determine if resistance testing in ART-naive HIV-positive pregnant women identified resistant mutations, which would modify our initial choice of therapy. A retrospective chart review was performed on all HIV-positive pregnant women seen from January 2000 to December 2001 at a university hospital. There were 72 pregnancies. Twenty-seven of 72 patients were ART naive. Genotype testing was performed in 18 of 27 naive patients. Three of 18 ART-naive patients (17%) had primary resistance (95% CI: 4%-41%) by genotype to NNRTIs. The primary mutation, G190S, conferring resistance to NNRTIs was present in 1 patient. Another had the K103N mutation. One had the K103R mutation, which conferred phenotypic resistance to NNRTIs by 8.3-fold, warranting a change in the initial regimen. In our community, resistance testing in ART-naive pregnant patients is warranted. Switching later to a more complex regimen during pregnancy may adversely affect adherence, resulting in virologic failure. Strategies to avoid prescribing a suboptimal regimen include waiting to initiate ART until the resistance testing results are available and/or beginning ART with a protease inhibitor-based regimen if the patient is already in the third trimester of pregnancy at the time of her initial clinic presentation.

Adolescent↗