New Non-nucleoside Reverse Transcriptase Inhibitors Research Articles

Synthesis and biological evaluation of cyclohexanpyridin-2(1H)-one analogues as novel HIV-1 NNRTIs

In the search and development of new non-nucleoside reverse transcriptase inhibitor (NNRTI) compounds that are more effective against HIV-1, eight C-4 alkylated cyclohexanpyridinone derivatives of the alkyloxy and alkylamino type were synthesized. Compounds were characterized by spectroscopic and spectrometric techniques. In addition, their inhibitory effect against reverse transcriptase (RT), inhibition of HIV in vitro and cytotoxicity in JLTRG cells was evaluated. Compound 8e showed reasonable cellular antiviral activity (EC50 = 28.78 μM), moderate inhibition against RT (IC50 = 69.8 μM), and was not cytotoxic at the concentrations evaluated. Docking and molecular dynamics studies corroborate favorable binding to the HIV IT allosteric site with 8e, providing a basis for the design of more potent analogues.

Efficacy and safety of ainuovirine versus efavirenz combination therapies with lamivudine/tenofovir disoproxil fumarate for medication of treatment-naïve HIV-1-positive adults: week 48 results of a randomized controlled phase 3 clinical trial followed by an open-label setting until week 96

Ainuovirine (ANV) is a new non-nucleoside reverse transcriptase inhibitor (NNRTI), which was initially synthesized in Korea and later further developed in both Korea and China. A randomized, double-blind, double-dummy, positive parallel group, non-inferiority, phase 3 trial was conducted in 7 sites across China. Eligible HIV-1-positive antiretroviral therapy (ART)-naïve adults aged 18-65 years were randomly assigned in a 1:1 ratio to receive tenofovir disoproxil fumarate and lamivudine (TDF+3TC) in combination with either ANV (ANV group) or efavirenz (EFV group) for up to 48 weeks. Subsequently, participants in both groups received one of the two drug combinations according to their choice until week 96 in an observational study under an open-label setting. The primary endpoint was the proportion of participants achieving HIV RNA <50 copies/mL at week 48, with non-inferiority pre-specified at a margin of 10%. The secondary efficacy endpoints were logarithmic changes in HIV RNA, percentage of participants with HIV RNA levels ≤400 copies/mL and changes in the CD4 T-cell count after 48 and 96 weeks of treatment, as well as the percentage of participants with HIV RNA levels <50 copies/mL at 96 weeks of treatment. Safety endpoints were the incidence of adverse events and laboratory abnormalities evaluated according to the Division of AIDS criteria. This study was registered with the Chinese Clinical Trial Registry (Registration number: ChiCTR1800019041). Between November 27, 2018 and March 11, 2021, a total of 826 participants were screened, and 630 were finally enrolled and randomly assigned (1:1) to either ANV (n=315) or EFV (n=315) groups. The mean age was 30.6±9.4 years and most participants were male (94.6%). At week 48, 274 (87.0%) of 315 participants in the ANV group and 288 (91.7%) of 314 in the EFV group achieved HIV-1 RNA <50 copies/mL and non-inferiority was established (difference:-4.7%, 95% CI:-9.6 to 0.1%). In the period, 293 participants continued to take the ANV regimen and 287 switched from the EFV to the ANV regimen. During the open-label period, 92.5% (271/293) of participants in the continued ANV group and 95.1% (273/287) in the ANV to EFV transfer group remained virologically suppressed (HIV-1 RNA <50 copies/mL) at week 96 (p=0.189). The incidence of NNRTI treatment-related adverse events (TEAEs) at week 48 was 67.6% in 315 participants in the ANV group, which was significantly lower than in 91.4% of 314 participants in the EFV group (p<0.001). The most common TEAEs (weeks 0-48) were dizziness (10.5%) and dyslipidemia (22.2%) in the ANV group vs. 51.0% and 34.4% in the EFV group, respectively, followed by transaminase elevation (9.2% vs. 29.0%), γ-glutamyl transferase elevation (8.3% vs. 19.1%), and rash (7.9% vs. 18.8%) (all p<0.001). After switching from EFV to ANV, TEAEs in the former EFV participants were significantly reduced in the following observational period of 48-96 weeks. The week 48 results indicated that the efficacy of ANV was non-inferior to EFV when combined with two NRTIs. The per-protocol risk difference at week 48 for the primary endpoint also supported non-inferiority. TEAEs in ANV treated participants were less frequent with regard to liver toxicity, dyslipidemia, neuropsychiatric symptoms and rash compared to the EFV group during the first 48 weeks of therapy. The effects were maintained during the 48-96 weeks of therapy. Jiangsu Aidea Pharmaceutical Co., Ltd.

Synthesis, In Vitro Anti-HIV Activity, Cytotoxicity, and Computational Studies of Some New Steroids and Their Pyrazoline and Oxime Analogues

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains by development of new non-nucleoside reverse transcriptase inhibitors (NNRTIs). A series of pregnenolone analogues, 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones, were synthesized. Further, treatment of 3-((4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-ones with thiosemicarbazide in ethanolic KOH or hydrazine hydrate in HOAc gave 5-(4-bromo-, 4-trifluoromethyl, or 4-methylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamides and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline, respectively. Analogously, treatment of 3-((4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one with hydroxylamine afforded the Z/E isomers of 3-(4-bromophenyl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one oxime. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 3-(thiophene-2-yl)-1-(preg-5-en-3β-ol-17-yl)prop-2-en-1-one and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline were the most active in inhibiting HIV-1 and HIV-2 with IC50 = 60.5 μM (SI > 2, against HIV-2 and SI 0.29 μM (SI < I), respectively, suggesting to be new leads in the development of antiviral agents. QSAR of 3-((aryl)-1-(5-pregnen-3β-ol-17-yl)prop-2-en-1-ones and 5-(substituted phenyl)-3-(5-preg-5-3β-ol-17-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamides has been studied. The conformational analysis of 5-(4-trifluoromethylphenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline-1-carbothioamide and 1-O-acetyl-(5-(4-bromophenyl)-3-(preg-5-en-3β-ol-17-yl)-4,5-dihydro-1H-pyrazoline as well as the molecular docking study of the latter compound have been investigated.

QSAR modeling of anti-HIV activity for DAPY-like derivatives using the mixture of ligand-receptor binding information and functional group features as a new class of descriptors

An accurate QSAR model was developed for the prediction of the anti-HIV activities of a set of DAPY-like derivatives as new non-nucleoside reverse transcriptase inhibitors (NNRTIs). The ligand–receptor (LR) interactions for all compounds were studied by the docking of compounds in the active site of appropriate receptors. The binding information of LR complexes at the best pose was called the molecular docking descriptors (MDDs). The mixture of 10 MDDs with about 154 simple, functional group counts was used as a new group of descriptors in the QSAR study of DAPY-like compounds. Among the 164 mixed descriptors, seven descriptors were selected as the most effective descriptors using the linear stepwise regression (SR) method and used as inputs of the artificial neural network (ANN) model. Levenberg–Marquardt (LM) method was used for the training of ANN through the backpropagation of errors algorithm. The Levenberg–Marquardt artificial neural network (LM-ANN) model with the architecture of 6-4-1 was selected as the optimal model. The predictability of the LM-ANN model was estimated by applying the external test set and the leave-one-out (LOO) method. The mean square errors (MSEs) and coefficient of determination (R2) values for the test set were 0.16 and 0.89, respectively. The Q2 value for the LOO method was calculated as 0.72. The results obtained demonstrated that a mixture of MDDs and functional group counts provided the required information for the construction of a QSAR model with acceptable prediction ability.

Combination of least absolute shrinkage and selection operator with Bayesian Regularization artificial neural network (LASSO-BR-ANN) for QSAR studies using functional group and molecular docking mixed descriptors

A combination of least absolute shrinkage and selection operator (LASSO) with Bayesian Regularization feed-forward artificial neural network (LASSO-BR-ANN) was used as a new approach in the quantitative structure-activity relationship (QSAR) studies. A mixture of the docking derived descriptors with the simple functional group (structural) features was also introduced as a new ensemble of descriptors for accurate QSAR modeling. The performance of introduced approaches was tested with QSAR modeling of the biological activities (pEC50) of 73 azine derivatives as new non-nucleoside reverse transcriptase inhibitors (NNRTIs) for treatment of HIV disease. Molecular docking descriptors (MDDs) were generated from ligand-receptor interactions and functional group features derived using Dragon 5.5 software. The dataset was divided into three sets of training, validation, and test data. LASSO, as a penalized regression method, was applied to the training data set for the selection of the most relevant descriptors among the mixture of the structural and MDDs. LASSO selected descriptors were used as inputs in the construction of the Bayesian Regularization artificial neural network (BR-ANN) model. The results showed that the addition of functional group properties to the MDDs improves the accuracy of the model. Under the optimum conditions, LASSO-BR-ANN was successfully applied for the prediction of PEC50 values for compounds in the external test set with mean square error (MSE) and coefficient of determination (R2) values of 0.07 and 0.88, respectively. Some of the prediction statistical parameters of the model were calculated and all of them were in their acceptable ranges, which confirm the validity of the proposed QSAR model.

Doravirine: a new non-nucleoside reverse transcriptase inhibitor for the treatment of HIV infection.

Doravirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that was approved by the United States Food and Drug Administration (FDA) on August 30, 2018, for the treatment of HIV infection in adult patients. The product was also approved in the E.U. and Japan in November 2018 and January 2020, respectively. It is currently available as a single stand-alone tablet as well as part of a single-tablet regimen in a fixed-dose combination with tenofovir disoproxil and lamivudine. Similarly to other NNRTIs, doravirine exerts its antiviral effect through a noncompetitive inhibition of HIV-1 reverse transcriptase. It has a novel resistance pathway so that it retains in vitro activity against clinically relevant NNRTI viral mutations K103N, Y181C and G190A. In randomized clinical trials, doravirine was noninferior to efavirenz- and darunavir-based regimens, with fewer adverse events. Doravirine has a more favorable drug interaction profile compared with earlier NNRTIs as it neither inhibits nor induces the cytochrome P450 3A4 (CYP3A4) enzyme. Doravirine has been added to the category of Recommended Initial Regimens in Certain Clinical Situations in the United States Department of Health and Human Services Antiretroviral Guidelines for Adults and Adolescents.

Doravirine: First Global Approval.

Doravirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) developed by Merck & Co for the treatment of HIV-1 infection. The drug is approved in the USA both as a single-agent tablet (Pifeltro™) and as a fixed-dose combination tablet with the nucleos(t)ide reverse transcriptase inhibitors lamivudine and tenofovir disoproxil fumarate (Delstrigo™). Each formulation is indicated in the USA for treating HIV-1 infection in adults with no prior antiretroviral treatment, has received a positive opinion in the EU for treating HIV-1 infection in adults without resistance to NNRTIs or (in the case of the fixed-dose combination tablet) lamivudine or tenofovir, and is also under regulatory review for the treatment of HIV-1 infection in Canada. This article summarizes the milestones in the development of doravirine leading to this first approval for the treatment of HIV-1 infection in treatment-naïve adults.

Diaryl ethers with carboxymethoxyphenacyl motif as potent HIV-1 reverse transcriptase inhibitors with improved solubility

In search of new non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved solubility, two series of novel diaryl ethers with phenacyl moiety were designed and evaluated for their HIV-1 reverse transcriptase inhibition potentials. All compounds exhibited good to excellent results with IC50 at low micromolar to submicromolar concentrations. Two most active compounds (7e and 7 g) exhibit inhibitory potency comparable or even better than that of nevirapine and rilpivirine. Furthermore, SupT1 and CD4+ cell infectivity assays for the most promising (7e) have confirmed its strong antiviral potential while docking studies indicate a novel binding interactions responsible for high activity.

2,6-Di(arylamino)-3-fluoropyridine Derivatives as HIV Non-Nucleoside Reverse Transcriptase Inhibitors.

New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine, 2,4-di(arylamino)-5-fluoropyrimidine, or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and practical synthesis of novel NNRTI relies on two sequential Pd-catalyzed aminations as the key steps. It is demonstrated through direct comparison with reference compounds that the presence of a fluorine atom increases the in vitro anti-HIV activity, both against the wild type virus and drug-resistant mutant strains.

CP-033 Monitoring off-label use of rilpivirine in a University Hospital

BackgroundRilpivirine (RPV) is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) approved only in treatment-naïve patients although it is commonly used in switch strategy due to its efficacy, lack of side...

Potencial papel de rilpivirina en el escenario de simplificación

Antiretroviral simplification is a useful strategy to improve adherence and quality of life and prevent or reverse adverse effects in patients with HIV infection. The availability of new drugs with high efficacy and better tolerability in once-daily formulations or in fixed-dose combinations may be a better option for prolonged treatment. Rilpivirine, a new nonnucleoside reverse transcriptase inhibitor (NNRTI), has shown high antiviral efficacy in clinical trials with treatment-naïve patients, with a lower incidence of adverse effects and good tolerability. Its use in simplification regimens has been evaluated after the switch from efavirenz, demonstrating that dose adjustment is not required. In a large randomized study in patients who were receiving protease inhibitors, virological efficacy was maintained, with a lower incidence of adverse effects and improved lipid parameters and cardiovascular risk score. Given the ease of administration and good tolerability of this drug, recent communications at congresses have shown the rapid applicability of the results of studies in daily clinical practice in this scenario.

Potential of the novel antiretroviral drug rilpivirine to modulate the expression and function of drug transporters and drug-metabolising enzymes in vitro

The objective of this study was to assess the drug–drug interaction potential of the new non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine in vitro. The following were evaluated: P-glycoprotein (P-gp/ABCB1) inhibition by calcein assay; breast cancer resistance protein (BCRP/ABCG2) inhibition by pheophorbide A efflux; and inhibition of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 by 8-fluorescein–cAMP uptake. Inhibition of cytochrome P450 enzymes was assessed using commercially available kits. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC transporters. Induction of drug-metabolising enzymes and transporters was quantified by real-time RT-PCR in LS180 cells, and activation of pregnane X receptor (PXR) by a reporter gene assay. Rilpivirine significantly inhibited P-gp (IC50=13.1±6.8μmol/L), BCRP (IC50=1.5±0.3μmol/L), OATP1B1 (IC50=4.1±1.8μmol/L), OATP1B3 (IC50=6.1±0.9μmol/L), CYP3A4 (IC50=1.3±0.6μmol/L), CYP2C19 (IC50=2.7±0.3μmol/L) and CYP2B6 (IC50=4.2±1.6μmol/L). Growth inhibition assays indicate that rilpivirine is not a substrate of P-gp, BCRP, or multidrug resistance-associated proteins 1 and 2. In LS180 cells, rilpivirine induced mRNA expression of ABCB1, CYP3A4 and UGT1A3, whereas ABCC1, ABCC2, ABCG2, OATP1B1 and UGT1A9 were not induced. Moreover, rilpivirine was a PXR activator. In conclusion, rilpivirine inhibits and induces several relevant drug-metabolising enzymes and drug transporters, but owing to its low plasma concentrations it is most likely less prone to drug–drug interactions than older NNRTIs.

Safety and efficacy of fixed‐dose combination rilpivirine‐tenofovir‐emtricitabine (RPV/TDF/FTC) in treatment‐experienced patients infected with HIV‐1

Purpose of the studyRilpivirine (RPV) is a new non‐nucleoside reverse transcriptase inhibitor (NNRTI) which has shown non‐inferiority to efavirenz (EFV) in terms of efficacy and safety profiles. The vast majority of clinical data has been performed in the treatment naïve population and has not been studied in depth in treatment‐experienced patients. We sought to explore the safety and efficacy of RPV/TDF/FTC in treatment‐experienced patients attending our clinics.MethodsHIV‐infected individuals commenced on RPV/TDF/FTC from December 2011 to June 2012 were retrospectively identified from a patient database. Patient demographics were extracted. Biochemical, virological and immunological parameters were collated. At baseline, 1 month and 3 month time points the following laboratory results were compared using the Kruskal‐Wallis test: CD4 count, HIV viral load, amino transferase (ALT), cholesterol, triglyceride and HDL/cholesterol ratio.Summary of resultsSixty‐five patients (4 female) were identified. Median age was 38 years (range: 25–73). Fifty‐six patients were treatment experienced (2 re‐start); 39 on NNRTI‐based (33 on EFV), 10 on PI‐based and 4 on other regimens. 9 patients were naïve to treatment. The reasons for switch are illustrated in Fig. 1. Fifty‐four patients had HIV‐RNA‐1&lt;40 copies/mL at the time of switch and all remained undetectable at 3 months. At baseline, the median CD4 count was 555 cells/mm3 (range: 209–1586) in the switch group, which increased significantly to 638 cells/mm3 (p&lt;0.005) 3 months after switch. Switch to RPV/TDF/FTC had a favorable effect on lipid profile. At baseline the median cholesterol, triglyceride and HDL/cholesterol ratio levels were 4.8 mmol/L, 1.78 mmol/L and 4.37 respectively. At 1 month post‐switch this decreased to 4.5 mmol/L, 1.65 mmol/L and 4.24 and at 3 months post‐switch decreased to 4.1 mmol/L, 1.44 mmol/L and 4.04. Median HIV‐RNA‐1 in treatment‐naïve patients (n=9) at baseline was 50298 copies/mL, at 1 month four patients had HIV‐RNA‐1&lt;40 copies/mL and at 3 months eight patients had HIV‐RNA‐1&lt;40 copies/mL. RPV/TDF/FTC had no favourable effect on lipid profile in treatment‐naïve group and had no effect on ALT levels in either the switch or the treatment‐naïve group.ConclusionIn this cohort, RPV/TDF/FTC has been shown to have a safe virological efficacy and safety profile as a switch therapy for patients suppressed on their current standard of care and are experiencing adverse events.image

Rilpivirine: a new non-nucleoside reverse transcriptase inhibitor

Rilpivirine is a new non-nucleoside reverse transcriptase inhibitor (NNRTI) that is approved for HIV-1 treatment-naive adult patients in combination with other antiretroviral agents. The recommended dose is a 25 mg tablet once daily taken orally with a meal. Due to cytochrome P450 3A4 enzyme induction or gastric pH increase, rilpivirine cannot be coadministered with a number of other drugs (anticonvulsants, rifabutin, rifampicin, rifapentine, proton pump inhibitors, systemic dexamethasone and St John's wort). Rilpivirine should be used with caution when coadministered with a drug with a known risk for torsade de pointes. Rilpivirine has a better tolerability than a comparative NNRTI, efavirenz, in clinical trials, with fewer central nervous system adverse effects, rashes, lipid abnormalities and discontinuation rates. Virological failure occurs more commonly with higher baseline viral loads (>100,000 copies/mL) and lower baseline CD4 counts (<50 cells/mm(3)). Seventeen NNRTI mutations have been associated with decreased susceptibility to rilpivirine: K101E/P, E138A/G/K/Q/R, V179L, Y181C/I/V, H221Y, F227C, M230I/L, Y188L and the combination L100I + K103N. Resistance to rilpivirine largely excludes future use of the NNRTI class.

Subunit-Selective Mutational Analysis and Tissue Culture Evaluations of the Interactions of the E138K and M184I Mutations in HIV-1 Reverse Transcriptase

The emergence of HIV-1 drug resistance remains a major obstacle in antiviral therapy. M184I/V and E138K are signature mutations of clinical relevance in HIV-1 reverse transcriptase (RT) for the nucleoside reverse transcriptase inhibitors (NRTIs) lamivudine (3TC) and emtricitabine (FTC) and the second-generation (new) nonnucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine (RPV), respectively, and the E138K mutation has also been shown to be selected by etravirine in cell culture. The E138K mutation was recently shown to compensate for the low enzyme processivity and viral fitness associated with the M184I/V mutations through enhanced deoxynucleoside triphosphate (dNTP) usage, while the M184I/V mutations compensated for defects in polymerization rates associated with the E138K mutations under conditions of high dNTP concentrations. The M184I mutation was also shown to enhance resistance to RPV and ETR when present together with the E138K mutation. These mutual compensatory effects might also enhance transmission rates of viruses containing these two mutations. Therefore, we performed tissue culture studies to investigate the evolutionary dynamics of these viruses. Through experiments in which E138K-containing viruses were selected with 3TC-FTC and in which M184I/V viruses were selected with ETR, we demonstrated that ETR was able to select for the E138K mutation in viruses containing the M184I/V mutations and that the M184I/V mutations consistently emerged when E138K viruses were selected with 3TC-FTC. We also performed biochemical subunit-selective mutational analyses to investigate the impact of the E138K mutation on RT function and interactions with the M184I mutation. We now show that the E138K mutation decreased rates of polymerization, impaired RNase H activity, and conferred ETR resistance through the p51 subunit of RT, while an enhancement of dNTP usage as a result of the simultaneous presence of both mutations E138K and M184I occurred via both subunits.

Synthesis and anti-HIV Activity of New Benzimidazole, Benzothiazole and Carbohyrazide Derivatives of the anti-Inflammatory Drug Indomethacin

There is an urgent need for the design and development of new and safer drugs for the treatment of HIV infection, active against the currently resistant viral strains. New derivatives of the non-steroidal anti-inflammatory drug indomethacin bearing benzimidazoles, benzothiazole, purine and pyridine residues 8 - 13 were synthesized with the aim of developing new non-nucleoside reverse transcriptase inhibitors (NNRTIs).Alternatively, new imine analogs 16 - 20 were synthesized from condensation of indomethacinyl hydrazide 15, prepared from the ester 14, with various ketone precursors. Treatment of 15 with phenyl isothiocyanate or triethyl orthoformate afforded the phenylcarbonothioyl and the oxadiazole derivatives 21 and 22, respectively. The new compounds were assayed against HIV-1 and HIV-2 in MT-4 cells. Compounds 9 and 10 were the most active in inhibiting HIV-2 and HIV-1, respectively, with EC50 ≥ 17.60 μgmL−1 and &gt; 1.15 μgmL−1 (therapeutic indexes (SI) of ≥ 3 and &lt; 1, respectively), and are leading candidates for further development.

268 Expression profile of genes influencing the efficiency of taxanes in breast cancer therapy

The objective of this study was to assess the drug–drug interaction potential of the new non-nucleoside reverse transcriptase inhibitor (NNRTI) rilpivirine in vitro. The following were evaluated: P-glycoprotein (P-gp/ABCB1) inhibition by calcein assay; breast cancer resistance protein (BCRP/ABCG2) inhibition by pheophorbide A efflux; and inhibition of organic anion transporting polypeptide (OATP) 1B1 and OATP1B3 by 8-fluorescein–cAMP uptake. Inhibition of cytochrome P450 enzymes was assessed using commercially available kits. Substrate characteristics were evaluated by growth inhibition assays in MDCKII cells overexpressing particular ABC transporters. Induction of drug-metabolising enzymes and transporters was quantified by real-time RT-PCR in LS180 cells, and activation of pregnane X receptor (PXR) by a reporter gene assay. Rilpivirine significantly inhibited P-gp (IC50 = 13.1 ± 6.8 μmol/L), BCRP (IC50 = 1.5 ± 0.3 μmol/L), OATP1B1 (IC50 = 4.1 ± 1.8 μmol/L), OATP1B3 (IC50 = 6.1 ± 0.9 μmol/L), CYP3A4 (IC50 = 1.3 ± 0.6 μmol/L), CYP2C19 (IC50 = 2.7 ± 0.3 μmol/L) and CYP2B6 (IC50 = 4.2 ± 1.6 μmol/L). Growth inhibition assays indicate that rilpivirine is not a substrate of P-gp, BCRP, or multidrug resistance-associated proteins 1 and 2. In LS180 cells, rilpivirine induced mRNA expression of ABCB1, CYP3A4 and UGT1A3, whereas ABCC1, ABCC2, ABCG2, OATP1B1 and UGT1A9 were not induced. Moreover, rilpivirine was a PXR activator. In conclusion, rilpivirine inhibits and induces several relevant drug-metabolising enzymes and drug transporters, but owing to its low plasma concentrations it is most likely less prone to drug–drug interactions than older NNRTIs.

Microdose Pharmacokinetics of IDX899 and IDX989, Candidate HIV‐1 Non‐Nucleoside Reverse Transcriptase Inhibitors, Following Oral and Intravenous Administration in Healthy Male Subjects

IDX899 and IDX989 are new non-nucleoside reverse-transcriptase inhibitors (NNRTIs) that exhibit potent inhibition of HIV-1 replication, including NNRTI-resistant mutants. This microdose study investigates the pharmacokinetics and determined oral bioavailability. For each compound, 4 healthy male subjects are randomized to receive via a crossover design a single 100-microg oral and intravenous dose together with 100 nCi of [(14)C]-labeled drug. Plasma and urine samples are obtained over a period of 168 hours postdose and analyzed for total, unchanged drug and major metabolites using an accelerator mass spectrometry method. Based on total radioactivity, oral absorption is near complete. For the parent drug, mean absolute bioavailability is 61% and 65% for IDX899 and IDX989, respectively. Both compounds are extensively metabolized especially after oral dosing. Observed terminal phase half-lives after oral and intravenous doses range from 4 to 10 hours and are comparable for the 2 compounds. Urine excretion of radioactivity for both compounds is less than 10%. These data show for the first time that IDX899 and IDX989 possess favorable pharmacokinetic properties in humans, including high mean absolute bioavailability and long half-life. IDX899 has been selected based on these initial pharmacokinetic assessments and other criteria as the candidate for further clinical development.

Polyisoprenylated Benzophenones from Clusiaceae: Potential Drugs and Lead Compounds

Many new polyisoprenylated benzophenones with a bicyclo[3.3.1]-nonane-2,4,9-trione core structure have been isolated from plants in the Clusiaceae family, and their potent biological properties have been the subject of several studies. This review summarizes the biological activities reported for these secondary metabolites including cytotoxic, antimicrobial, antioxidant, and anti-inflammatory activities. Our efforts during the past years have foremost been directed towards isolating new polyisoprenylated benzophenones, as well as understanding the possible target and mechanism of action through which these compounds arrest cancer cells and inhibit the progression of the cell-cycle. The transcription of genes is affected in cancer cells treated with polyisoprenylated benzophenones; the oncogene c-Myb is down-regulated and endoplasmatic stress genes XBP1, ATF4, and DDIT3/CHOP are turned on. Consequently, the expression of iNOS and cell cycle regulators such as cyclin D and E are reduced. Evidence presented by independent investigators suggests that polyisoprenylated benzophenones affect the mediators in the Akt/mTOR stress pathway, although the specific target remains to be discovered. In addition, benzophenones isolated from plants display high antioxidant capacity and protect cells from oxidative stress and the formation of ROS involved during the inflammatory process. Since antiviral activity was initially reported for guttiferone A, potent synthetic analogues have been developed as effective new non-nucleoside reverse transcriptase inhibitors (NNRTI) to treat drug resistant HIV-1. In addition, benzophenones exert antimicrobial effects particularly against MRSA. The structure-activity relationships of polyisoprenylated benzophenones from natural sources and those of synthetic analogues are included in this review. Absorption, metabolism, and elimination of benzophenones are also discussed.

Etravirine and Rilpivirine: Nonnucleoside Reverse Transcriptase Inhibitors with Activity Against Human Immunodeficiency Virus Type 1 Strains Resistant to Previous Nonnucleoside Agents

Etravirine and rilpivirine are two new nonnucleoside reverse transcriptase inhibitors (NNRTIs) that have the distinct advantage of being able to be used in patients with exposure to previous NNRTIs (e.g., nevirapine or efavirenz). Etravirine was approved by the United States Food and Drug Administration to be used twice/day in treatment-experienced patients infected with the human immunodeficiency virus. The approval was based on phase III clinical studies in which 61% of etravirine-treated patients reached an undetectable viral load of less than 50 copies/ml compared with 40% of patients who received the optimized background regimen. Etravirine was well tolerated with a self-limiting skin rash being the most common toxicity, reported in 19% of patients. Rilpivirine, a once-daily NNRTI, is entering phase III studies; the drug appears to be effective against a broad range of NNRTI-resistant viruses including etravirine-resistant strains.