Etravirine

In the current landscape of antiretroviral options, there remains an urgent need for novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) with improved resistance profiles and safety properties. Herein, a series of novel tetrahydropyrido[4,3- d ]pyrimidine derivatives were discovered utilizing the "escape from flatland" strategy. The most potent inhibitor 10c was endowed with broad-spectrum antiviral activity and improved resistance profiles against NNRTI-resistant variants compared to efavirenz and etravirine...

HIV-1 reverse transcriptase is one of the most attractive targets for the treatment of AIDS. However, the rapid emergence of drug-resistant strains and unsatisfactory drug-like properties seriously limit the clinical application of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Here we show that a series of piperazine sulfonyl-bearing diarylpyrimidine-based NNRTIs were designed to improve the potency against wild-type and NNRTI-resistant strains by enhancing backbone-binding interactions. Among them, compound 18b1 demonstrates single-digit nanomolar potency against the wild-type and five mutant HIV-1 strains, which is significantly better than the approved drug etravirine...

BACKGROUND: Most of the safety data of clobazam came from well-designed clinical trials, while the real-world information is insufficient. RESEARCH DESIGN AND METHODS: We performed a disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database and conducted a systematic review of case reports regarding adverse drug reactions (ADR) linked to clobazam. RESULTS: The analysis of FAERS identified 595 ADR signals. Nervous system disorders were the most frequent reported positive signals...

To enhance the anti-resistance efficacy of our previously reported non-nucleoside reverse transcriptase inhibitor (NNRTI) 4 , a series of novel biphenyl-DAPY derivatives were developed using the fragment-hopping strategy. Most of the compounds 8a-v exhibited remarkably improved anti-HIV-1 potency. The most active compound 8r proved to be exceptionally potent against the wild-type HIV-1 (EC50 = 2.3 nM) and five mutant strains, such as K103N (EC50 = 8 nM) and E138K (EC50 = 6 nM), significantly better than 4 ...

OBJECTIVE: To assess the virological outcomes, prevalence of HIV drug resistance mutation (DRM) and correlates in Butuo County. METHODS: We conducted a cross-sectional study. Virological failure (VF) was defined as HIV-1 RNA ≥1000 copies/ml and on Antiretroviral therapy (ART) for ≥6 months. Genotypic drug resistance was performed among VF cases. Correlates of DRM were identified using multivariate logistic regression. RESULTS: The overall virological suppression rate was 85...

BACKGROUND: Doravirine shows a rather distinct resistance profile within the NNRTI class. This study aimed to evaluate the phenotypic susceptibility to doravirine, rilpivirine and etravirine in a panel of multidrug-resistant (MDR) HIV-1 isolates collected from people living with HIV (PLWH) enrolled in the PRESTIGIO Registry. METHODS: Recombinant viruses expressing PLWH derived protease-reverse transcriptase coding region were generated from plasma samples at virological failure with documented resistance to PIs, NRTIs, NNRTIs and INSTIs...

Although non-nucleoside reverse transcriptase inhibitors (NNRTIs) exhibit potent anti-HIV-1 activity and play an important role in the active antiretroviral therapy of AIDS, the emergence of drug-resistant strains has seriously reduced their clinical efficacy. Here, we report a series of 2,4,5-trisubstituted pyrimidines as potent HIV-1 NNRTIs by exploiting the tolerant regions of the NNRTI binding pocket. Compounds 16b and 16c were demonstrated to have excellent activity (EC50 = 3.14-22.1 nM) against wild-type and a panel of mutant HIV-1 strains, being much superior to that of etravirine (EC50 = 3...

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) represent cornerstones of current regimens for treatment of human immunodeficiency virus type 1 (HIV-1) infections. However, NNRTIs usually suffer from low aqueous solubility and the emergence of resistant viral strains. In the present work, novel bicyclic NNRTIs derived from etravirine (ETV) and rilpivirine (RPV), bearing modified purine, tetrahydropteridine, and pyrimidodiazepine cores, were designed and prepared. Compounds 2 , 4 , and 6 carrying the acrylonitrile moiety displayed single-digit nanomolar activities against the wild-type (WT) virus (EC50 = 2...

Here, we reported a novel series of "dual-site" binding diarylpyrimidine (DAPY) derivatives targeting both the NNRTI adjacent site and NNRTIs binding pocket (NNIBP). The anti-HIV-1 activity results demonstrated that compound 9e (EC50  = 2.04-61.1 nM) displayed robust potencies against a panel of HIV-1 NNRTIs-resistant strains, being comparable to that of etravirine (ETR). Moreover, 9e displayed much lower cytotoxicity (CC50  = 59.2 μM) and higher SI values (4605) toward wild-type HIV-1 strain...

OBJECTIVE: To assess the efficacy of raltegravir, etravirine, and darunavir/ritonavir in treatment-experienced HIV-1 patients by describing the proportion of patients who experienced virological failure (VF) at W24. Secondary objectives were to follow HIV-1 plasma viral load (pVL) after W24, the proportion of patients who underwent dual/monotherapy and death. METHODS: Patients from the ANRS CO3 Aquitaine Cohort who were prescribed TRIO regimen between February 2007 and September 2018 were classified into 2 groups based on their pVL at inclusion: the virological failure group (VFG) with pVL>50 copies/mL and the virologically suppressed group (VSG) with pVL<50 copies/mL...

Herein, via crystallographic overlay-based molecular hybridization strategy, a series of disubstituted pyrimidine-5-carboxamide derivatives were designed by introducing an amide moiety to the central core of the lead etravirine. All the newly synthesized compounds were evaluated for their anti-HIV-1 potencies in MT-4 cells using the MTT method. Most of the synthesized compounds displayed promising antiviral activities against the wild-type (IIIB) and a panel of HIV-1 NNRTIs-resistant strains. Especially, 21c exhibited the most potent activity (EC50  = 0...

In this study, privileged boronic acid ester was introduced into the right wing of etravirine (ETR) to obtain a series of novel boronate-containing derivatives. These newly synthesized derivatives were evaluated for their anti-HIV potency in MT-4 cells using the MTT method, and their inhibitory activity to HIV-1 reverse transcriptase (RT) was assayed by the ELISA method. Most of the synthesized compounds displayed promising antiviral activity against the wild-type and a wide range of HIV-1 mutant strains. In particular, 4a exhibited the most potent activity against the wild-type and a panel of single mutations (L100I, K103N, Y181C, and E138K) with EC50 values ranging from 0...

Multiple factors may affect combined antiretroviral therapy (cART). We investigated the impact of food, beverages, dietary supplements, and alcohol on the pharmacokinetic and pharmacodynamic parameters of 33 antiretroviral drugs. Systematic review in adherence to PRISMA guidelines was performed, with 109 reports of 120 studies included. For each drug, meta-analyses or qualitative analyses were conducted. We have found clinically significant interactions with food for more than half of antiretroviral agents...

INTRODUCTION: ACTG A5288 was a strategy trial conducted in diverse populations from multiple continents of people living with HIV (PLWH) failing second-line protease inhibitor (PI)-based antiretroviral therapy (ART) from 10 low- and middle-income countries (LMICs). Participants resistant to lopinavir (LPV) and/or multiple nucleotide reverse transcriptase inhibitors started on third-line regimens that included raltegravir (RAL), darunavir/ritonavir (DRV/r) and/or etravirine (ETR) according to their resistance profiles...

BACKGROUND: Etravirine (ETR) is approved as a component of second or third-line antiretroviral treatment (ART) for children living with HIV. We assessed the outcomes of ETR-based ART in children in routine care in Europe and Thailand. METHODS: Data on children aged <18 years at ETR start were pooled from 17 observational cohorts. Characteristics at ETR start, immunological and virological outcomes at 12 months, discontinuations, adverse events (AEs) and serious adverse events (SAEs) were described...

The present investigation aims to develop and explore mannosylated lipid-based carriers to deliver an anti-HIV drug, Etravirine (TMC) and Selenium nanoparticles (SeNPs), to the HIV reservoirs via the mannose receptor. The successful mannosylation was evaluated by the change in zeta potential and lectin binding assay using fluorescence microscopy. Electron microscopy and scattering studies were employed to study the structure and surface of the nanocarrier system. The presence of selenium at the core-shell of the nanocarrier system was confirmed by X-ray photoelectron spectroscopy and energy dispersive X-ray analysis...

This letter describes the first synthetic methodology for phenoxypyrimidines that avoids the direct use of phenols or their salts. In contrast to the general trend of delivering Suzuki-Miyaura cross-coupling products in reactions between aryl or alky halides and arylboronic acids, the substrate pairs used herein (chloropyrimidines and arylboronic acids) led to C-O bond formation under the reaction conditions. In total, 25 phenoxypyrimidines were successfully synthesized using the described protocol, 6 of which had a structural resemblance to etravirine...

OBJECTIVE: The aim of this study was to evaluate HIV-1 drug resistance among patients failing first-line antiretroviral therapy in Ethiopia. METHOD: A total of 699 HIV-infected adults (≥15 years) who failed first-line ART were recruited between 2017 and 2019 from 63 ART-providing sites in Ethiopia. Treatment failure was defined as patients with two consecutive viral loads ≥1000 copies/ml within 6 months of follow-up. The pol gene region of HIV-1 was amplified and sequenced using in-house assay of China CDC...

Etravirine is an antiviral whose oral absorption is limited by low solubility/dissolution. The objective was to predict and compare etravirine's surfactant-mediated dissolution into polyoxyethylene-10 lauryl ether (POE) and FeSSIF-V2, including the contribution of slow micelle diffusivity. Dynamic light scattering (DLS) was used to measure the size and diffusivity values of drug-loaded micelles. In vitro intrinsic dissolution into surfactant media were predicted using a model for surfactant-mediated dissolution...

To thoroughly investigate the uncharted chemical space around the entrance channel of HIV-1 reverse transcriptase (RT) and to improve the physicochemical properties, we introduced different spiro ring structures with high Fsp3 values as linkers at indole-2-carboxamide, attaching to various terminal substituents to enhance the interactions with the entrance channel. All the newly designed and synthesized indolylarylsulfone (IAS) derivatives exhibited moderate to excellent potency against wild-type HIV-1 with EC50 values ranging from 0...