The Experts below are selected from a list of 120 Experts worldwide ranked by ideXlab platform

Karla G. Childers - One of the best experts on this subject based on the ideXlab platform.

  • Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor.
    The Journal of organic chemistry, 2016
    Co-Authors: Jeffrey T. Kuethe, Guy R. Humphrey, Michel Journet, Zhihui Peng, Karla G. Childers
    Abstract:

    The development of a practical asymmetric total synthesis of the potent HIV-1 Integrase Inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.

H Murai - One of the best experts on this subject based on the ideXlab platform.

  • The discovery of S/GSK1265744: a carbamoyl pyridone HIV-1 Integrase Inhibitor
    Journal of the International AIDS Society, 2012
    Co-Authors: Y Taoda, B Johns, J Weatherhead, D Temelkoff, T Kawasuji, H Yoshida, T Taishi, R Kiyama, M Fuji, H Murai
    Abstract:

    Background: HIV-1 Integrase is a virally encoded enzyme essential for lentiviral replication. Assiduous medicinal chemistry efforts culminated in the discovery of raltegravir, the first marketed HIV-1 Integrase Inhibitor (INI). However, there is significant opportunity for improvement including overall dose burden, dosing interval and potency against resistant viruses. Our molecular design approach used a two-metal binding pharmacophore strategy and succeeded in identification of carbamoyl pyridone HIV-1 INIs. This enriched core scaffold has abundant structural features expanding the opportunity to control drug properties, leading to the discovery of S/GSK1265744. Methods: The carbamoyl pyridone scaffold was derivatized and evaluated for antiviral activity against wild-type virus (±HSA) along with key INI-resistant mutants. Animal pharmacokinetic profiles including a key measure of the trough drug concentration over protein-adjusted antiviral potency (C24/PAIC50) along with in vitro DMPK properties, were used along with the virological data for compound selection. Results: The carbamoyl pyridone series Inhibitors exhibited potent antiviral profiles with promising DMPK properties. S/GSK1265744 demonstrated good coverage of C24 over PAIC50 predicting low mg unboosted once daily dosing, now validated in phase 2 clinical studies. These preclinical data along with a long human T1/2 of ~30 hours in oral tablet study supports S/GSK1265744 as a long acting parenteral agent for once-monthly or less frequent dosing. Conclusions: A medicinal chemistry approach utilizing key viral mutants in combination with C24/PAIC50 has allowed for discovery of S/GSK1265744. This agent is currently in phase 2 development evaluating a novel, long-acting parenteral route of administration and may enable new approaches to HIV therapy and prevention

  • The discovery of S/GSK1265744: a carbamoyl pyridone HIV-1 Integrase Inhibitor
    Journal of the International AIDS Society, 2012
    Co-Authors: Y Taoda, B Johns, D Temelkoff, T Kawasuji, H Yoshida, T Taishi, R Kiyama, M Fuji, H Murai, T Yoshinaga
    Abstract:

    Background : HIV-1 Integrase is a virally encoded enzyme essential for lentiviral replication. Assiduous medicinal chemistry efforts culminated in the discovery of raltegravir, the first marketed HIV-1 Integrase Inhibitor (INI). However, there is significant opportunity for improvement including overall dose burden, dosing interval and potency against resistant viruses. Our molecular design approach used a two-metal binding pharmacophore strategy and succeeded in identification of carbamoyl pyridone HIV-1 INIs. This enriched core scaffold has abundant structural features expanding the opportunity to control drug properties, leading to the discovery of S/GSK1265744. Methods : The carbamoyl pyridone scaffold was derivatized and evaluated for antiviral activity against wild-type virus (±HSA) along with key INI-resistant mutants. Animal pharmacokinetic profiles including a key measure of the trough drug concentration over protein-adjusted antiviral potency (C24/PAIC 50 ) along with in vitro DMPK properties, were used along with the virological data for compound selection. Results :The carbamoyl pyridone series Inhibitors exhibited potent antiviral profiles with promising DMPK properties. S/GSK1265744 demonstrated good coverage of C24 over PAIC 50 predicting low mg unboosted once daily dosing, now validated in phase 2 clinical studies. These preclinical data along with a long human T 1/2 of ~30 hours in oral tablet study supports S/GSK1265744 as a long acting parenteral agent for once-monthly or less frequent dosing. Conclusions : A medicinal chemistry approach utilizing key viral mutants in combination with C24/PAIC 50 has allowed for discovery of S/GSK1265744. This agent is currently in phase 2 development evaluating a novel, long-acting parenteral route of administration and may enable new approaches to HIV therapy and prevention. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Taoda Y et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18267 http://www.jiasociety.org/index.php/jias/article/view/18267 | http://dx.doi.org/10.7448/IAS.15.6.18267

Y Taoda - One of the best experts on this subject based on the ideXlab platform.

  • The discovery of S/GSK1265744: a carbamoyl pyridone HIV-1 Integrase Inhibitor
    Journal of the International AIDS Society, 2012
    Co-Authors: Y Taoda, B Johns, J Weatherhead, D Temelkoff, T Kawasuji, H Yoshida, T Taishi, R Kiyama, M Fuji, H Murai
    Abstract:

    Background: HIV-1 Integrase is a virally encoded enzyme essential for lentiviral replication. Assiduous medicinal chemistry efforts culminated in the discovery of raltegravir, the first marketed HIV-1 Integrase Inhibitor (INI). However, there is significant opportunity for improvement including overall dose burden, dosing interval and potency against resistant viruses. Our molecular design approach used a two-metal binding pharmacophore strategy and succeeded in identification of carbamoyl pyridone HIV-1 INIs. This enriched core scaffold has abundant structural features expanding the opportunity to control drug properties, leading to the discovery of S/GSK1265744. Methods: The carbamoyl pyridone scaffold was derivatized and evaluated for antiviral activity against wild-type virus (±HSA) along with key INI-resistant mutants. Animal pharmacokinetic profiles including a key measure of the trough drug concentration over protein-adjusted antiviral potency (C24/PAIC50) along with in vitro DMPK properties, were used along with the virological data for compound selection. Results: The carbamoyl pyridone series Inhibitors exhibited potent antiviral profiles with promising DMPK properties. S/GSK1265744 demonstrated good coverage of C24 over PAIC50 predicting low mg unboosted once daily dosing, now validated in phase 2 clinical studies. These preclinical data along with a long human T1/2 of ~30 hours in oral tablet study supports S/GSK1265744 as a long acting parenteral agent for once-monthly or less frequent dosing. Conclusions: A medicinal chemistry approach utilizing key viral mutants in combination with C24/PAIC50 has allowed for discovery of S/GSK1265744. This agent is currently in phase 2 development evaluating a novel, long-acting parenteral route of administration and may enable new approaches to HIV therapy and prevention

  • The discovery of S/GSK1265744: a carbamoyl pyridone HIV-1 Integrase Inhibitor
    Journal of the International AIDS Society, 2012
    Co-Authors: Y Taoda, B Johns, D Temelkoff, T Kawasuji, H Yoshida, T Taishi, R Kiyama, M Fuji, H Murai, T Yoshinaga
    Abstract:

    Background : HIV-1 Integrase is a virally encoded enzyme essential for lentiviral replication. Assiduous medicinal chemistry efforts culminated in the discovery of raltegravir, the first marketed HIV-1 Integrase Inhibitor (INI). However, there is significant opportunity for improvement including overall dose burden, dosing interval and potency against resistant viruses. Our molecular design approach used a two-metal binding pharmacophore strategy and succeeded in identification of carbamoyl pyridone HIV-1 INIs. This enriched core scaffold has abundant structural features expanding the opportunity to control drug properties, leading to the discovery of S/GSK1265744. Methods : The carbamoyl pyridone scaffold was derivatized and evaluated for antiviral activity against wild-type virus (±HSA) along with key INI-resistant mutants. Animal pharmacokinetic profiles including a key measure of the trough drug concentration over protein-adjusted antiviral potency (C24/PAIC 50 ) along with in vitro DMPK properties, were used along with the virological data for compound selection. Results :The carbamoyl pyridone series Inhibitors exhibited potent antiviral profiles with promising DMPK properties. S/GSK1265744 demonstrated good coverage of C24 over PAIC 50 predicting low mg unboosted once daily dosing, now validated in phase 2 clinical studies. These preclinical data along with a long human T 1/2 of ~30 hours in oral tablet study supports S/GSK1265744 as a long acting parenteral agent for once-monthly or less frequent dosing. Conclusions : A medicinal chemistry approach utilizing key viral mutants in combination with C24/PAIC 50 has allowed for discovery of S/GSK1265744. This agent is currently in phase 2 development evaluating a novel, long-acting parenteral route of administration and may enable new approaches to HIV therapy and prevention. (Published: 11 November 2012) Citation: Abstracts of the Eleventh International Congress on Drug Therapy in HIV Infection Taoda Y et al. Journal of the International AIDS Society 2012, 15 (Suppl 4):18267 http://www.jiasociety.org/index.php/jias/article/view/18267 | http://dx.doi.org/10.7448/IAS.15.6.18267

Steven L Chuck - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment experienced patients with hiv 1 receiving a ritonavir boosted protease Inhibitor randomised double blind phase 3 non inferiority study
    Lancet Infectious Diseases, 2012
    Co-Authors: Jeanmichel Molina, Anthony Lamarca, Jaime Andradevillanueva, Bonaventura Clotet, Nathan Clumeck, Yapei Liu, Lijie Zhong, Nicolas A Margot, Andrew K Cheng, Steven L Chuck
    Abstract:

    Summary Background Elvitegravir is a once daily Inhibitor of HIV-1 Integrase boosted by ritonavir. We aimed to compare the efficacy and safety of elvitegravir with raltegravir, another HIV-1 Integrase Inhibitor, in patients in whom previous antiretroviral treatment failed. Methods We conducted a randomised, double-blind, double-dummy, phase 3 study at 234 sites in 13 countries. Eligible patients had plasma HIV RNA of 1000 copies per mL or greater, any CD4 cell count, and resistance to or 6 months' experience with at least two classes of antiretroviral drugs. They received an open-label background regimen of a fully active, ritonavir-boosted protease Inhibitor and a second agent. We randomly allocated patients (1:1) by computer with a block size of four to receive either elvitegravir 150 mg once daily (n=361; 85 mg dose if given with atazanavir, or lopinavir with ritonavir) or raltegravir 400 mg twice daily (n=363). Placebo tablets were given to mask the difference in daily dosing. The primary endpoint was achievement and maintenance of virological response (HIV RNA Findings Ten patients allocated elvitegravir and 12 assigned raltegravir were excluded from the analysis (either for protocol violations or because they did not receive treatment). 207 (59%) of 351 patients allocated elvitegravir achieved virological response compared with 203 (58%) of 351 assigned raltegravir (treatment difference 1·1%, 95% CI −6·0 to 8·2), meeting the criterion for non-inferiority (p=0·001). Three patients allocated elvitegravir had serious adverse events related to study drugs compared with seven assigned raltegravir; two and eight patients died, respectively. More individuals assigned elvitegravir reported diarrhoea up to week 48 (p=0·023), and more patients assigned raltegravir had grade 3 or 4 rises in alanine aminotransferase (p=0·020) or aspartate aminotransferase (p=0·009). Interpretation Elvitegravir used in combination with a ritonavir-boosted protease Inhibitor in treatment-experienced patients has similar efficacy and safety to raltegravir. Since elvitegravir can be given once a day compared with twice a day for raltegravir, elvitegravir might improve patients' adherence. Funding Gilead Sciences.

Jeffrey T. Kuethe - One of the best experts on this subject based on the ideXlab platform.

  • Asymmetric Synthesis of a Potent HIV-1 Integrase Inhibitor.
    The Journal of organic chemistry, 2016
    Co-Authors: Jeffrey T. Kuethe, Guy R. Humphrey, Michel Journet, Zhihui Peng, Karla G. Childers
    Abstract:

    The development of a practical asymmetric total synthesis of the potent HIV-1 Integrase Inhibitor 5 is described. Key transformations include construction of the naphthridine core in a highly efficient manner followed by cyclization of the 8-membered ring. Control of the atropisomers of intermediates and final compound 5 is also described.