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121.
Cliff C. Cheng Gerald W. Shipps Zhiwei Yang Noriyuki Kawahata Charles A. Lesburg José S. Duca Jamie Bandouveres Jack D. Bracken Chuan-kui Jiang Sony Agrawal Eric Ferrari H.-C. Huang 《Bioorganic & medicinal chemistry letters》2010,20(7):2119-2124
SAR exploration from an initial hit, (S)-N-(2-cyclohexenylethyl)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)benzamide (1), identified using our proprietary automated ligand identification system (ALIS),1 has led to a novel series of selective hepatitis C virus (HCV) NS5B polymerase inhibitors with improved in vitro potency as exemplified by (S)-2-fluoro-6-(2-(1-hydroxy-3-phenylpropan-2-ylamino)-2-oxoethoxy)-N-isopentyl-N-methylbenzamidecarboxamide (41) (IC50 = 0.5 μM). The crystal structure of an analogue (44) was solved and provided rationalization of the SAR of this series, which binds in a distinct manner in the palm domain of NS5B, consistent with biochemical analysis using enzyme mutant variants. These data warrant further lead optimization efforts on this novel series of non-nucleoside inhibitors targeting the HCV polymerase. 相似文献
122.
Matthew G. Stanton Jed Hubbs David Sloman Christopher Hamblett Paula Andrade Minilik Angagaw Grace Bi Regina M. Black Jamie Crispino Jonathan C. Cruz Eric Fan Georgia Farris Bethany L. Hughes Candia M. Kenific Richard E. Middleton George Nikov Peter Sajonz Sanjiv Shah Nirah Shomer Alexander A. Szewczak Benito Munoz 《Bioorganic & medicinal chemistry letters》2010,20(2):755-758
We report herein a novel series of difluoropiperidine acetic acids as modulators of γ-secretase. Synthesis of 2-aryl-3,3-difluoropiperidine analogs was facilitated by a unique and selective β-difluorination with Selectfluor®. Compounds 1f and 2c were selected for in vivo assessment and demonstrated selective lowering of Aβ42 in a genetically engineered mouse model of APP processing. Moreover, in a 7-day safety study, rats treated orally with compound 1f (250 mg/kg per day, AUC0–24 = 2100 μM h) did not exhibit Notch-related effects. 相似文献
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124.
Andrew R. Whiteley Kim Hastings John K. Wenburg Chris A. Frissell Jamie C. Martin Fred W. Allendorf 《Conservation Genetics》2010,11(5):1929-1943
Following glacial recession in southeast Alaska, waterfalls created by isostatic rebound have isolated numerous replicate
populations of coastal cutthroat trout (Oncorhynchus clarkii clarkii) in short coastal streams. These replicate isolated populations offer an unusual opportunity to examine factors associated
with the maintenance of genetic diversity. We used eight microsatellites to examine genetic variation within and differentiation
among 12 population pairs sampled from above and below these natural migration barriers. Geological evidence indicated that
the above-barrier populations have been isolated for 8,000–12,500 years. Genetic differentiation among below-barrier populations
(F
ST = 0.10, 95% C.I. 0.08–0.12) was similar to a previous study of more southern populations of this species. Above-barrier populations
were highly differentiated from adjacent below-barrier populations (mean pairwise F
ST = 0.28; SD 0.18) and multiple lines of evidence were consistent with asymmetric downstream gene flow that varied among streams.
Each above-barrier population had reduced within-population genetic variation when compared to the adjacent below-barrier
population. Within-population genetic diversity was significantly correlated with the amount of available habitat in above-barrier
sites. Increased genetic differentiation of above-barrier populations with lower genetic diversity suggests that genetic drift
has been the primary cause of genetic divergence. Long-term estimates of N
e based on loss of heterozygosity over the time since isolation were large (3,170; range 1,077–7,606) and established an upper
limit for N
e if drift were the only evolutionary process responsible for loss of genetic diversity. However, it is likely that a combination
of mutation, selection, and gene flow have also contributed to the genetic diversity of above-barrier populations. Contemporary
above-barrier N
e estimates were much smaller than long-term N
e estimates, not correlated with within-population genetic diversity, and not consistent with the amount of genetic variation
retained, given the approximate 10,000-year period of isolation. The populations isolated by waterfalls in this study that
occur in larger stream networks have retained substantial genetic variation, which suggests that the amount of habitat in
headwater streams is an important consideration for maintaining the evolutionary potential of isolated populations. 相似文献
125.
Yong-jig Cho Jonathan D. Meade Blake R. Shester Jamie C. Walden Zhen Guo Peng Liang 《Biotechnology letters》2010,32(11):1593-1597
We have determined the linear dynamic range in signal detection by Fluorescent Differential Display (FDD) using conditionally
induced mRNA expression of the p53 tumor-suppressor gene as a control. By serial spiking of p53-induced RNA into that of non-induced
RNA, we were able to quantitatively measure up to 100-fold change in p53 mRNA expression level. The linear dynamic range of
signal detection per mRNA message was determined to be from 1000 up to 20,000 in fluorescence signal, in which the signals
for the majority of mRNAs reside. Thus, FDD can be used to accurately quantify differences in mRNA expression among eukaryotic
cells. 相似文献
126.
Investigating the phase behavior of sugars in ice and lyophilized solids is of significant interest in the pharmaceutical industry. In this study, Raman and near infrared (NIR) spectroscopy are used to characterize and quantitate trehalose crystallization using several chemometric models. The predictive behaviors of partial least squares (PLS), principal component analysis (PCA), and multiple linear regression (MLR) models are compared. In general, PLS and PCA outperform linear and MLR models. Changes in specific vibrational modes associated with several coupled motions are described and assigned as a function of crystal content. In addition to characterization and quantitation, our method may be used to localize gradients of amorphous and/or crystallized trehalose within a sample. 相似文献
127.
128.
i-Motif-forming sequences are present in or near the regulatory regions of >40% of all genes, including known oncogenes. We report here the results of a biophysical characterization and computational study of an ensemble of intramolecular i-motifs that model the polypyrimidine sequence in the human c-MYC P1 promoter. Circular dichroism results demonstrate that the mutant sequence (5′-CTT TCC TAC CCTCCC TAC CCT AA-3′) can adopt multiple “i-motif-like,” classical i-motif, and single-stranded structures as a function of pH. The classical i-motif structures are predominant in the pH range 4.2-5.2. The “i-motif-like” and single-stranded structures are the most significant species in solution at pH higher and lower, respectively, than that range. Differential scanning calorimetry results demonstrate an equilibrium mixture of at least three i-motif folded conformations with Tm values of 38.1, 46.6, and 49.5°C at pH 5.0. The proposed ensemble of three folded conformations includes the three lowest-energy conformations obtained by computational modeling and two folded conformers that were proposed in a previous NMR study. The NMR study did not report the most stable conformer found in this study. 相似文献
129.
130.