The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains ...encompassing genotypes 1–6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure–activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38–108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.
Oxime derivatives of the sordarin aglycone have been identified as potent antifungal agents. The in vitro spectrum of activity includes coverage against Candida albicans and Candida glabrata with ...MICs as low as 0.06 microg/mL. The antifungal activity was established to be exquisitely sensitive to the spatial orientation of the lipophilic side chains.
We report the observation of the exclusive decay Bs0-->Ds-Ds+ at the 7.5 standard deviation level using 355 pb(-1) of data collected by the CDF II detector in pp collisions at sqrts=1.96 TeV at the ...Fermilab Tevatron. We measure the relative branching ratio B(Bs0-->Ds-Ds+)/B(B0-->D-Ds+)=1.44(-0.44)(+0.48). Using the world average value for B(B0-->D-Ds+), we find B(Bs0-->Ds-Ds+)=(9.4(-4.2)(+4.4))x10(-3). This provides a lower bound DeltaGammasCP/Gammas>or=2B(Bs0-->Ds-Ds+)>1.2x10(-2) at 95% C.L.
The synthesis and biological activity of sordarin oxazepine derivatives are described. The key step features a regioselective oxidation of an unprotected triol followed by double reductive amination ...to afford the ring-closed products. The spectrum of antifungal activity for these novel derivatives includes coverage of
Candida albicans,
Candida glabrata, and
Cryptococcus neoformans.
The synthesis and antifungal activity of sordarin oxazepine derivatives are described.
Objective: To investigate the relationships between fitness and components of the metabolic syndrome in sedentary men. Subjects and Methods: 39 subjects (34–53 years) were evaluated for fitness ...(v̇O2max) and anthropometric, metabolic, and skeletal muscle phenotypes. v̇O2max was assessed on a bicycle ergometer whereas other variables were obtained from an oral glucose tolerance test (OGTT), hydrostatic weighing, and a muscle biopsy. Results: Pearson and partial correlations adjusted for fat mass (FM), waist circumference (WC), muscle enzyme activities (citrate synthase (CS), cytochrome c oxidase (COX)), and capillary density were used to investigate the independent relationships be tween variables. Negative correlations between v̇O2max and WC as well as blood pressure and OGTT test were observed. When adjusted for FM, correlations remained between v̇O2max and WC (r = –0.46, p < 0.01) and systolic blood pressure (r = –0.35, p < 0.05). When adjusted for WC and CS activity, all correlations were lost except for high-sensitivity C-reactive protein (hs-CRP) (r = –0.34, p < 0.05) which remained when adjusted for CS activity. Adjustment for COX activity failed to remove correlations with hs-CRP (r = –0.36, p < 0.05), age (r = 0.34, p < 0.05), WC (r = –0.35, p < 0.05), and blood pressure. Negative correlations persisted when fitness was adjusted for the mean number of capillaries. Conclusion: The effects of fitness on components of the metabolic syndrome in sedentary men are explained by abdominal obesity and muscle phenotypes.
The synthesis and antifungal activity of 5′- and 5′-6′-substituted azasordarin derivatives are described. Modification of the 5′-position led to the discovery of the spirocyclopentyl analogue
7g, ...which is the first azasordarin to register single-digit MIC values versus
Aspergillus spp. Further investigation identified the 5′-
i-Pr derivative
7b, which displays superior pharmacokinetic properties compared to other azasordarins.
The synthesis and antifungal activity of novel azasordarin derivatives are described.
Both 6‘- and 4‘-fluoro-glycosylated indolo2,3-acarbazoles are substrates for base-induced loss of fluorine as a leaving group from sp3 carbon. In the case of α-N-glycosylated substrate 3, loss of ...fluorine from the 6‘-position leads to 3,6-anhydroglucose analogue 1. A novel N12,N13-bridged sugar analogue 2 results from loss of 4‘-fluorine from β-N-glycosylated analogue 4. Both analogues 1 and 2 display topo I inhibitory potencies similar to camptothecin.
Associations between glycogen synthase gene (GYS1) polymorphism and states of insulin resistance and type 2 diabetes have been reported. The purpose of this study was to establish if the GYS1 ...genotype impacts on the content of glycogen synthase (GS) protein in muscle measured under basal and stimulated conditions. To examine this, GYS1 XbaI and Met416Val polymorphisms and thigh muscle GYS1 protein content were determined at rest, both before and after several weeks of neuromuscular electrical stimulation in carriers and noncarriers of the mutations. The allelic frequency was 0.086 for the XbaI mutation (A2) and 0.006 for the Met416Val in our cohort of French-Canadian subjects. When measured at rest, the GS protein content in muscle was similar among carriers and noncarriers of the XbaI variant. However, the stimulation-induced increase (23%) in the amount of GS muscle protein normally seen in wildtype individuals was impaired in those carrying the XbaI mutation. These data demonstrate that some individuals, because of their genetic background, are unable to stimulate the process of GS protein accumulation in skeletal muscle. These results could explain why some individuals appear to be genetically predisposed to developing skeletal muscle insulin resistance when exposed to unfavorable metabolic environments.
The Collider Detector at Fermilab collected a unique sample of jets originating from bottom-quark fragmentation (b-jets) by selecting online proton-antiproton (pp¯) collisions with a vertex displaced ...from the pp¯ interaction point, consistent with the decay of a bottom-quark hadron. This data set, collected at a center-of-mass energy of 1.96 TeV, and corresponding to an integrated luminosity of 5.4 fb−1, is used to measure the Z-boson production cross section times branching ratio into bb¯. The number of Z→bb¯ events is determined by fitting the dijet-mass distribution, while constraining the dominant b-jet background, originating from QCD multijet events, with data. The result, σ(pp¯→Z)×B(Z→bb¯)=1.11±0.08(stat)±0.14(syst) nb, is the most precise measurement of this process, and is consistent with the standard-model prediction. The data set is also used to search for Higgs-boson production. No significant signal is expected in our data and the first upper limit on the cross section for the inclusive pp¯→H→bb¯ process at s=1.96 TeV is set, corresponding to 33 times the expected standard-model cross section, or σ=40.6 pb, at the 95% confidence level.
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