The Experts below are selected from a list of 558 Experts worldwide ranked by ideXlab platform
William W Freimuth - One of the best experts on this subject based on the ideXlab platform.
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effect of food on the steady state pharmacokinetics of Delavirdine in patients with hiv infection
Clinical Drug Investigation, 2003Co-Authors: Gene D. Morse, Margaret A Fischl, Mark J. Shelton, Steve R. Cox, Andrew A Dellacoletta, Leslie Thompson, William W FreimuthAbstract:In a prior single-dose study that examined the effect of food on Delavirdine pharmacokinetics in healthy volunteers, the absorption of Delavirdine mesylate was delayed and the area under the curve was reduced by 26% in the presence of food. Since the complex, nonlinear pharmacokinetics of Delavirdine do not permit a simple extrapolation of the results of a single-dose study to steady state, the present multiple-dose study was performed. Thirteen stable patients with HIV-1 infection (two females, 11 males; CD4 count range 124–588 cells/mm3) completed a randomised, crossover study in which subjects received two 14-day treatments with Delavirdine mesylate 400mg every 8 hours. In treatment A, all Delavirdine doses were administered on an empty stomach and in treatment B were taken with food. A pharmacokinetic evaluation was performed on day 14 of each treatment period. An ambulatory AIDS research centre in an academic medical centre. Administration of Delavirdine with and without food. Pharmacokinetic parameters for Delavirdine. The maximum concentration (Cmax) [± standard deviation] in treatment A was 29.6 ± 13.6μM and in treatment B it was 23.0 ± 8.61μM (p = 0.037). The minimum concentrations (Cmin) were 9.45 ± 6.7μM and 11.2 ± 9.2μM, respectively (p > 0.05). The oral clearances (CLoral) were 17.8 ± 41.6 L/h (treatment A) and 18.5 ± 39.0 L/h (treatment B) [p > 0.05]. Similar patterns were observed for N-dealkylated Delavirdine with a significant difference only in Cmax (4.13 vs 3.47μM [p = 0.022], treatment A vs B). These findings indicated that, in contrast to the increased CLoral noted in a prior single-dose study, food did not have a significant effect at steady state on the area under the plasma concentration-time curve or Cmin. Although Cmax was significantly lower when the drug was taken taken with food, the clinical relevance of this parameter as compared with the trough concentration is unclear since the current focus for antiretrovirals is on maintaining trough concentrations in excess of in vitro inhibitory concentrations.
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multiple dose pharmacokinetics of Delavirdine mesylate and didanosine in hiv infected patients
Clinical Drug Investigation, 2003Co-Authors: Gene D. Morse, William W Freimuth, Mark J. Shelton, Steven R Cox, Andrew A Dellacoletta, Susan E Cohn, Carol Greisberger, Richard C ReichmanAbstract:Background: Delavirdine is a non-nucleoside reverse transcriptase inhibitor with pH-dependent absorption characteristics that has received accelerated approval for the treatment of patients with HIV-1 infection. In a prior single-dose study concurrent administration of Delavirdine mesylate and didanosine (buffered formulation) resulted in up to a 31% decrease in the area under the plasma Delavirdine concentration versus time curve (AUC) compared with when both drugs were taken separately.
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randomized study of saquinavir with ritonavir or nelfinavir together with Delavirdine adefovir or both in human immunodeficiency virus infected adults with virologic failure on indinavir aids clinical trials group study 359
The Journal of Infectious Diseases, 2000Co-Authors: Roy M Gulick, Stephen W Lagakos, Susan A Fiscus, Courtney V Fletcher, Richard Haubrich, Hailong Cheng, Edward P Acosta, Ronald Swanstrom, William W FreimuthAbstract:This study compared antiretroviral activity among 6 salvage therapy regimens. The study was a prospective, randomized, 2 × 3 factorial, multicenter study of the AIDS Clinical Trials Group. The study enrolled 277 human immunodeficiency virus (HIV)-infected patients naive to nonnucleoside analogues who had taken indinavir >6 months. The patients had 2000-200,000 HIV RNA copies/mL. Patients received saquinavir with ritonavir or nelfinavir together with Delavirdine andlor adefovir and were followed for safety and antiretroviral response between baseline and week 16. At week 16, 30% (77/254) of patients had ≤500 HIV RNA copies/mL. Virologic response did not differ significantly between pooled ritonavir and nelfinavir groups (28% vs. 33%; P =.50) or between pooled Delavirdine and Delavirdine/adefovir groups (40% vs. 33%; P =.42). Pooled Delavirdine groups had a greater virologic response rate than did adefovir groups (40% vs. 18%; P =.002). Overall, one-third of patients who experienced virologic failure on an indinavir-containing regimen suppressed virus load levels while they were taking a new salvage regimen.
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Delavirdine susceptibilities and associated reverse transcriptase mutations in human immunodeficiency virus type 1 isolates from patients in a phase i ii trial of Delavirdine monotherapy actg 260
Antimicrobial Agents and Chemotherapy, 2000Co-Authors: Lisa M Demeter, William W Freimuth, Margaret A Fischl, Michael F Para, Patricia M Meehan, Jeanne Holdenwiltse, Robert W Shafer, Richard C ReichmanAbstract:The development of human immunodeficiency virus type 1 resistance to Delavirdine (DLV) was studied in subjects receiving DLV monotherapy. Phenotypic resistance developed in 28 of 30 subjects within 8 weeks. K103N and Y181C, which confer nonnucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, were the predominant reverse transcriptase mutations. P236L, which confers DLV resistance but hypersensitivity to other NNRTIs, developed in
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efficacy and safety of Delavirdine mesylate with zidovudine and didanosine compared with two drug combinations of these agents in persons with hiv disease with cd4 counts of 100 to 500 cells mm3 actg 261
Journal of Acquired Immune Deficiency Syndromes, 1999Co-Authors: Gerald Friedland, William W Freimuth, Gene D. Morse, Richard B Pollard, Lisa M Demeter, Brigitte P Griffith, Michael Hughes, Roland L Bassett, Elizabeth Connick, Thomas NevinAbstract:To evaluate the antiretroviral activity of Delavirdine mesylate, a nonnucleoside reverse transcriptase inhibitor of HIV-1, we performed a phase II, randomized, double-blind, multicenter trial comparing the three-drug combination of Delavirdine with zidovudine and didanosine to two-drug combinations of these drugs. Patients with CD4 cell counts between 100 and 500 cells/mm3 without prior or <6 months of monotherapy with zidovudine or didanosine were randomized to one of four arms and observed on a follow-up basis for 48 weeks. In total, 544 patients were evaluated. In those assigned to the three-drug regimen, mean short-term (weeks 4-12) and long-term (weeks 40-48) change in CD4 cells from baseline were 49.3 ± 8.1 and 65.4 ± 13.4 cells/mm3, respectively; mean short-term and long-term HIV-1 RNA changes from baseline were -1.13 log10 ± 0.12 and -0.73 ± 0.12 copies/ml, respectively. These responses in CD4 cell counts and HIV-1 RNA levels were better in comparisons with each of the two-drug arms at all study points; however, differences were not consistently significant. Gastrointestinal side effects were experienced by 33% of patients (178 of 544), and 30% (121 of 407) receiving Delavirdine experienced rash, only one case of which was severe. In this study, therapy with Delavirdine + zidovudine + didanosine was safe and showed modest, but not always significant, antiviral activity and CD4 cell count benefit compared with two-drug regimens with these agents.
Gene D. Morse - One of the best experts on this subject based on the ideXlab platform.
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interactions between buprenorphine and antiretrovirals i the nonnucleoside reverse transcriptase inhibitors efavirenz and Delavirdine
Clinical Infectious Diseases, 2006Co-Authors: Elinore F Mccancekatz, Gene D. Morse, Patrick F Smith, Gerald Friedland, David E Moody, Patricia Pade, Jennifer Baker, Anika Alvanzo, Abayomi B Ogundele, Peter JatlowAbstract:This study examined drug interactions between buprenorphine, an opioid partial agonist medication used in the treatment of opioid dependence, and the nonnucleoside reverse-transcriptase inhibitors (NNRTIs) efavirenz (EFV) and Delavirdine (DLV). Opioid-dependent, buprenorphine/naloxone-maintained, human immunodeficiency virus (HIV)-negative volunteers (n=10 per NNRTI) participated in 24-h sessions to determine pharmacokinetics of buprenorphine and of buprenorphine with either EFV or DLV after administration of standard doses of either antiretroviral for 15 or 7 days, respectively. Opiate withdrawal symptoms, cognitive effects, and adverse events were determined before and after antiretroviral administration in opioid-dependent participants. The pharmacokinetics of NNRTIs in healthy control participants were used to determine the effect of buprenorphine on NNRTIs. EFV decreased the buprenorphine area under the concentration-time curve (P<.001). DLV increased buprenorphine concentrations (P<.001). Clinically significant consequences of these interactions were not observed. Buprenorphine did not alter antiretroviral pharmacokinetics. Adjustments of doses of either buprenorphine or EFV or DLV are not likely to be necessary when these drugs are administered for the treatment of opiate dependence and HIV disease.
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pharmacokinetics of ritonavir and Delavirdine in human immunodeficiency virus infected patients
Antimicrobial Agents and Chemotherapy, 2003Co-Authors: Mark J. Shelton, Gene D. Morse, Ross G. Hewitt, Steven R Cox, John Clarke Adams, Andrew A DellacolettaAbstract:To evaluate the pharmacokinetic effect of adding Delavirdine mesylate to the antiretroviral regimens of human immunodeficiency virus (HIV)-infected patients stabilized on a full dosage of ritonavir (600 mg every 12 h), 12 HIV-1-infected subjects had Delavirdine mesylate (400 mg every 8 h) added to their current antiretroviral regimens for 21 days. Ritonavir pharmacokinetics were evaluated before (day 7) and after (day 28) the addition of Delavirdine, and Delavirdine pharmacokinetics were evaluated on day 28. The mean values (± standard deviations) for the maximum concentration in serum ( C max ) of ritonavir, the area under the concentration-time curve from 0 to 12 h (AUC 0-12 ), and the minimum concentration in serum ( C min ) of ritonavir before the addition of Delavirdine were 14.8 ± 6.7 μM, 94 ± 36 μM · h, and 3.6 ± 2.1 μM, respectively. These same parameters were increased to 24.6 ± 13.9 μM, 154 ± 83 μM · h, and 6.52 ± 4.85 μM, respectively, after the addition of Delavirdine ( P is C max of 23 ± 16 μM, an AUC 0-8 of 114 ± 75 μM · h, and a C min of 9.1 ± 7.5 μM. Therefore, Delavirdine increases systemic exposure to ritonavir by 50 to 80% when the drugs are coadministered.
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Delavirdine malabsorption in HIV-infected subjects with spontaneous gastric hypoacidity.
The Journal of Clinical Pharmacology, 2003Co-Authors: Mark J. Shelton, Ross G. Hewitt, John M. Adams, Steve R. Cox, James H. Chambers, Gene D. MorseAbstract:To determine the impact of gastric hypoacidity and acidic beverages on Delavirdine mesylate pharmacokinetics in HIV-infected subjects, matched subjects with (n = 11) and without (n = 10) gastric hypoacidity received Delavirdine 400 mg tid with either water or an acidic beverage (usually orange juice). The pharmacokinetics of Delavirdine and its N-desalkyl metabolite were determined over 8 hours after 14 days of each treatment. Gastric pH was measured at baseline and during each pharmacokinetic evaluation. Delavirdine exposure (Cmax, AUC0-->8 h, and Cmin) was approximately 50% lower and the extent of Delavirdine metabolism was higher in subjects with gastric hypoacidity. Orange juice produced a lower mean gastric pH compared to water and increased Delavirdine absorption by 50% to 70% in subjects with gastric hypoacidity. However, orange juice had a marginal impact on Delavirdine exposure in subjects without gastric hypoacidity. HIV-infected subjects with gastric hypoacidity significantly malabsorb Delavirdine. Delavirdine administration with acidic beverages improves, but dose not normalize, absorption in these subjects.
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multiple dose pharmacokinetics of Delavirdine mesylate and didanosine in hiv infected patients
Clinical Drug Investigation, 2003Co-Authors: Gene D. Morse, William W Freimuth, Mark J. Shelton, Steven R Cox, Andrew A Dellacoletta, Susan E Cohn, Carol Greisberger, Richard C ReichmanAbstract:Background: Delavirdine is a non-nucleoside reverse transcriptase inhibitor with pH-dependent absorption characteristics that has received accelerated approval for the treatment of patients with HIV-1 infection. In a prior single-dose study concurrent administration of Delavirdine mesylate and didanosine (buffered formulation) resulted in up to a 31% decrease in the area under the plasma Delavirdine concentration versus time curve (AUC) compared with when both drugs were taken separately.
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effect of food on the steady state pharmacokinetics of Delavirdine in patients with hiv infection
Clinical Drug Investigation, 2003Co-Authors: Gene D. Morse, Margaret A Fischl, Mark J. Shelton, Steve R. Cox, Andrew A Dellacoletta, Leslie Thompson, William W FreimuthAbstract:In a prior single-dose study that examined the effect of food on Delavirdine pharmacokinetics in healthy volunteers, the absorption of Delavirdine mesylate was delayed and the area under the curve was reduced by 26% in the presence of food. Since the complex, nonlinear pharmacokinetics of Delavirdine do not permit a simple extrapolation of the results of a single-dose study to steady state, the present multiple-dose study was performed. Thirteen stable patients with HIV-1 infection (two females, 11 males; CD4 count range 124–588 cells/mm3) completed a randomised, crossover study in which subjects received two 14-day treatments with Delavirdine mesylate 400mg every 8 hours. In treatment A, all Delavirdine doses were administered on an empty stomach and in treatment B were taken with food. A pharmacokinetic evaluation was performed on day 14 of each treatment period. An ambulatory AIDS research centre in an academic medical centre. Administration of Delavirdine with and without food. Pharmacokinetic parameters for Delavirdine. The maximum concentration (Cmax) [± standard deviation] in treatment A was 29.6 ± 13.6μM and in treatment B it was 23.0 ± 8.61μM (p = 0.037). The minimum concentrations (Cmin) were 9.45 ± 6.7μM and 11.2 ± 9.2μM, respectively (p > 0.05). The oral clearances (CLoral) were 17.8 ± 41.6 L/h (treatment A) and 18.5 ± 39.0 L/h (treatment B) [p > 0.05]. Similar patterns were observed for N-dealkylated Delavirdine with a significant difference only in Cmax (4.13 vs 3.47μM [p = 0.022], treatment A vs B). These findings indicated that, in contrast to the increased CLoral noted in a prior single-dose study, food did not have a significant effect at steady state on the area under the plasma concentration-time curve or Cmin. Although Cmax was significantly lower when the drug was taken taken with food, the clinical relevance of this parameter as compared with the trough concentration is unclear since the current focus for antiretrovirals is on maintaining trough concentrations in excess of in vitro inhibitory concentrations.
Xinyong Liu - One of the best experts on this subject based on the ideXlab platform.
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the journey of hiv 1 non nucleoside reverse transcriptase inhibitors nnrtis from lab to clinic
Journal of Medicinal Chemistry, 2019Co-Authors: Vigneshwaran Namasivayam, Murugesan Vanangamudi, Sonali Kurup, Victor G Kramer, Peng Zhan, Xinyong Liu, Jacob Kongsted, Siddappa N ByrareddyAbstract:Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), Delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clini...
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The Journey of HIV‑1 Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) from Lab to Clinic
2018Co-Authors: Vigneshwaran Namasivayam, Murugesan Vanangamudi, Sonali Kurup, Victor G Kramer, Peng Zhan, Xinyong Liu, Jacob Kongsted, Siddappa N ByrareddyAbstract:Human immunodeficiency virus (HIV) infection is now pandemic. Targeting HIV-1 reverse transcriptase (HIV-1 RT) has been considered as one of the most successful targets for the development of anti-HIV treatment. Among the HIV-1 RT inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTIs) have gained a definitive place due to their unique antiviral potency, high specificity, and low toxicity in antiretroviral combination therapies used to treat HIV. Until now, >50 structurally diverse classes of compounds have been reported as NNRTIs. Among them, six NNRTIs were approved for HIV-1 treatment, namely, nevirapine (NVP), Delavirdine (DLV), efavirenz (EFV), etravirine (ETR), rilpivirine (RPV), and doravirine (DOR). In this perspective, we focus on the six NNRTIs and lessons learned from their journey through development to clinical studies. It demonstrates the obligatory need of understanding the physicochemical and biological principles (lead optimization), resistance mutations, synthesis, and clinical requirements for drugs
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fused heterocycles bearing bridgehead nitrogen as potent hiv 1 nnrtis part 4 design synthesis and biological evaluation of novel imidazo 1 2 a pyrazines
European Journal of Medicinal Chemistry, 2015Co-Authors: Boshi Huang, Erik De Clercq, Peng Zhan, Wenmin Chen, Christophe Pannecouque, Xin Liang, Tao Liu, Yueyue Sun, Huiqing Liu, Xinyong LiuAbstract:Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 μM and 0.32 μM respectively, comparable to Delavirdine (DLV, EC50 = 0.54 μM) and nevirapine (NVP, EC50 = 0.31 μM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies.
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design synthesis and anti hiv evaluation of novel diarylnicotinamide derivatives danas targeting the entrance channel of the nnrti binding pocket through structure guided molecular hybridization
European Journal of Medicinal Chemistry, 2014Co-Authors: Zhaoqiang Liu, Erik De Clercq, Peng Zhan, Wenmin Chen, Christophe Pannecouque, Xinyong LiuAbstract:Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0.027 μM, SI > 12518) and 6b5 (EC50 = 0.029 μM, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 μM) and Delavirdine (EC50 = 0.66 μM). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed.
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synthesis and biological evaluation of piperidine substituted triazine derivatives as hiv 1 non nucleoside reverse transcriptase inhibitors
European Journal of Medicinal Chemistry, 2012Co-Authors: Xuwang Chen, Erik De Clercq, Peng Zhan, Christophe Pannecouque, Jan Balzarini, Xinyong LiuAbstract:Abstract A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC 50 values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC 50 values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.
Erik De Clercq - One of the best experts on this subject based on the ideXlab platform.
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hybrid chemistry part 4 discovery of etravirine vrx 480773 hybrids as potent hiv 1 non nucleoside reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Yafeng Wang, Erik De Clercq, Dirk Daelemans, Fener Chen, Huri Piao, Christophe PannecouqueAbstract:Abstract A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50 = 0.24 , SI >1225), was more potent than Delavirdine (EC50 = 0.66 μM, SI >67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
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fused heterocycles bearing bridgehead nitrogen as potent hiv 1 nnrtis part 4 design synthesis and biological evaluation of novel imidazo 1 2 a pyrazines
European Journal of Medicinal Chemistry, 2015Co-Authors: Boshi Huang, Erik De Clercq, Peng Zhan, Wenmin Chen, Christophe Pannecouque, Xin Liang, Tao Liu, Yueyue Sun, Huiqing Liu, Xinyong LiuAbstract:Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 μM and 0.32 μM respectively, comparable to Delavirdine (DLV, EC50 = 0.54 μM) and nevirapine (NVP, EC50 = 0.31 μM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies.
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Recent developments in the chemotherapy of HIV infect ions
2015Co-Authors: Erik De ClercqAbstract:Abstract: The HIV replicative cycle reveals several virus-specific events that could function as targets for chemotherapeutic intervention. The compounds that are presently available as anti-HIV drugs are targeted at either the substrate binding site of the reverse transcriptase (zidovudine, didanosine, zalcitabine, stavudine, lamivudine) or a non-substrate binding site of the reverse transcriptase (nevirapine, Delavirdine), or the viral protease (saquinavir, ritonavir, indinavir, nelfinavir). Various other compounds targeted at either the reverse transcriptase or viral protease are still under clinical development, and so are a number of compounds that interact with other targets of the HIV replicative cycle. Remarkable clinical efficacy has been observed with combinations of different reverse transcriptase inhibitors and protease inhibitors. It may be anticipated that with the advent of newer and more efficient compounds the effectiveness of HIV inhibition could still be improved upon and the prospects for a definitive cure of the disease may be accomplished
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design synthesis and anti hiv evaluation of novel diarylnicotinamide derivatives danas targeting the entrance channel of the nnrti binding pocket through structure guided molecular hybridization
European Journal of Medicinal Chemistry, 2014Co-Authors: Zhaoqiang Liu, Erik De Clercq, Peng Zhan, Wenmin Chen, Christophe Pannecouque, Xinyong LiuAbstract:Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0.027 μM, SI > 12518) and 6b5 (EC50 = 0.029 μM, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 μM) and Delavirdine (EC50 = 0.66 μM). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed.
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synthesis and biological evaluation of piperidine substituted triazine derivatives as hiv 1 non nucleoside reverse transcriptase inhibitors
European Journal of Medicinal Chemistry, 2012Co-Authors: Xuwang Chen, Erik De Clercq, Peng Zhan, Christophe Pannecouque, Jan Balzarini, Xinyong LiuAbstract:Abstract A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC 50 values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC 50 values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.
Christophe Pannecouque - One of the best experts on this subject based on the ideXlab platform.
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hybrid chemistry part 4 discovery of etravirine vrx 480773 hybrids as potent hiv 1 non nucleoside reverse transcriptase inhibitors
Bioorganic & Medicinal Chemistry, 2015Co-Authors: Yafeng Wang, Erik De Clercq, Dirk Daelemans, Fener Chen, Huri Piao, Christophe PannecouqueAbstract:Abstract A novel series of etravirine–VRX-480773 hybrids were designed using structure-guided molecular hybridization strategy and fusing the pharmacophore templates of etravirine and VRX-480773. The anti-HIV-1 activity and cytotoxicity was evaluated in MT-4 cell cultures. The most active hybrid compound in this series, N-(2-chlorophenyl)-2-((4-(4-cyano-2,6-dimethylphenoxy)pyrimidin-2-yl)thio)acetamide 3d (EC50 = 0.24 , SI >1225), was more potent than Delavirdine (EC50 = 0.66 μM, SI >67) in the anti-HIV-1 in vitro cellular assay. Studies of structure-activity relationships established a correlation between anti-HIV activity and the substitution pattern of the acetanilide group.
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fused heterocycles bearing bridgehead nitrogen as potent hiv 1 nnrtis part 4 design synthesis and biological evaluation of novel imidazo 1 2 a pyrazines
European Journal of Medicinal Chemistry, 2015Co-Authors: Boshi Huang, Erik De Clercq, Peng Zhan, Wenmin Chen, Christophe Pannecouque, Xin Liang, Tao Liu, Yueyue Sun, Huiqing Liu, Xinyong LiuAbstract:Through a structure-guided core-refining approach, a series of novel imidazo[1,2-a]pyrazine derivatives were designed, synthesized and evaluated as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Biological results of antiviral assay in MT-4 cell cultures showed that 12 target compounds displayed moderate activities against wild-type (wt) HIV-1 strain (IIIB) with EC50 values ranging from 0.26 μM to 19 μM. Among them, 4a and 5a were found to be the two most active analogues possessing EC50 values of 0.26 μM and 0.32 μM respectively, comparable to Delavirdine (DLV, EC50 = 0.54 μM) and nevirapine (NVP, EC50 = 0.31 μM) in a cell-based assay. Additionally, 9 compounds showed RT inhibitory activity superior to that of NVP. Moreover, some predicted drug-like properties of representative compounds 4a and 5a, as well as the structure-activity relationship (SAR) analysis were discussed in detail. The binding mode of compound 4a was investigated by molecular simulation studies.
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design synthesis and anti hiv evaluation of novel diarylnicotinamide derivatives danas targeting the entrance channel of the nnrti binding pocket through structure guided molecular hybridization
European Journal of Medicinal Chemistry, 2014Co-Authors: Zhaoqiang Liu, Erik De Clercq, Peng Zhan, Wenmin Chen, Christophe Pannecouque, Xinyong LiuAbstract:Through a structure-based molecular hybridization approach, a novel series of diarylnicotinamide derivatives (DANAs) targeting the entrance channel of HIV-1 NNRTIs binding pocket (NNIBP) were rationally designed, synthesized and evaluated for their anti-HIV activities in MT-4 cells together with the inhibition against the reverse transcriptase (RT) in an enzymatic assay. Encouragingly, most of the new DANAs were found to be active against wild-type HIV-1 with an EC50 in the range of 0.027-4.54 μM. Among them, compound 6b11 (EC50 = 0.027 μM, SI > 12518) and 6b5 (EC50 = 0.029 μM, SI = 2471) were identified as the most potent inhibitors, which were more potent than the reference drugs nevirapine (EC50 = 0.31 μM) and Delavirdine (EC50 = 0.66 μM). Some DANAs were also active at micromolar concentrations against the K103N + Y181C resistant mutant. Compound 6b11 exhibited the highest enzymatic inhibition activity (IC50 = 20 nM), which is equal to that of efavirenz (EC50 = 20 nM) and 31 times higher than that of nevirapine (EC50 = 0.62 μM). Preliminary structure-activity relationships (SARs) and molecular modeling of these new DANAs have been discussed.
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synthesis and biological evaluation of piperidine substituted triazine derivatives as hiv 1 non nucleoside reverse transcriptase inhibitors
European Journal of Medicinal Chemistry, 2012Co-Authors: Xuwang Chen, Erik De Clercq, Peng Zhan, Christophe Pannecouque, Jan Balzarini, Xinyong LiuAbstract:Abstract A novel series of piperidine-substituted triazine derivatives have been synthesized and evaluated for anti-HIV activities in MT-4 cells. Most compounds displayed extremely promising activity against wild-type HIV-1 with EC 50 values in low nanomolar concentration, better than that of Nevirapine, Delavirdine, Zidovudine and Dideoxycitidine, and higher potency towards the resistant mutant strain K103N/Y181C than that of Nevirapine and Delavirdine. Selected compounds were also assayed against reverse transcriptase with lower IC 50 values than that of Nevirapine. The structure-activity relationship (SAR) of these novel structural congeners was also discussed.