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排序方式: 共有211条查询结果,搜索用时 31 毫秒
61.
Zhijian Zhao William H. Leister Julie A. O’Brien Wei Lemaire David L. Williams Marlene A. Jacobson Cyrille Sur Gene G. Kinney Doug J. Pettibone Philip R. Tiller Sheri Smith George D. Hartman Craig W. Lindsley Scott E. Wolkenberg 《Bioorganic & medicinal chemistry letters》2009,19(5):1488-1491
Employing an iterative analogue library approach, novel potent and selective glycine transporter 1 (GlyT1) inhibitors containing a 4-pyridin-2-ylpiperidine sulfonamide have been discovered. These inhibitors are devoid of time-dependent CYP inhibition activity and exhibit improved aqueous solubility versus the corresponding 4-phenylpiperidine analogues. 相似文献
62.
Carmen D. Samuel‐Hodge Larry F. Johnston Ziya Gizlice Beverly A. Garcia Sara C. Lindsley Kathy P. Bramble Trisha E. Hardy Alice S. Ammerman Patricia A. Poindexter Julie C. Will Thomas C. Keyserling 《Obesity (Silver Spring, Md.)》2009,17(10):1891-1899
Low‐income women in the United States have the highest rates of obesity, yet they are seldom included in weight loss trials. To address this research gap, components of two evidence‐based weight loss interventions were adapted to create a 16‐week intervention for low‐income women (Weight Wise Program), which was evaluated in a randomized trial with the primary outcome of weight loss at 5‐month follow‐up. Participants were low‐income women (40–64 years) with a BMI of 25–45. Of 143 participants, 72 were randomized to the Weight Wise Program (WWP) and 71 to the Control Group (CG). Five‐month follow‐up data were obtained from 64 (89%) WWP and 62 (87%) CG participants. With baseline values carried forward for missing data, WWP participants had a weight change of ?3.7 kg compared to 0.7 kg in the CG (4.4 kg difference, 95% confidence interval (CI), 3.2–5.5, P < 0.001). For systolic blood pressure (SBP), change in the WWP was ?6.5 mm Hg compared to ?0.4 mm Hg among controls (6.2 mm Hg difference, 95% CI, 1.7–10.6, P = 0.007); for diastolic BP (DBP), changes were ?4.1 mm Hg for WWP compared to ?1.3 mm Hg for controls (2.8 mm Hg difference, 95% CI, 0.0–5.5, P = 0.05). Of the 72 WWP participants, 64, 47, and 19% lost at least 3, 5, and 7% of their initial body weight, respectively. In conclusion, the WWP was associated with statistically significant and clinically important short‐term weight loss. 相似文献
63.
Hemaka A. Rajapakse Philippe G. Nantermet Harold G. Selnick James C. Barrow Georgia B. McGaughey Sanjeev Munshi Stacey R. Lindsley Mary Beth Young Phung L. Ngo M. Katherine Holloway Ming-Tain Lai Amy S. Espeseth Xiao-Ping Shi Dennis Colussi Beth Pietrak Ming-Chih Crouthamel Katherine Tugusheva Qian Huang Min Xu Adam J. Simon Joseph P. Vacca 《Bioorganic & medicinal chemistry letters》2010,20(6):1885-1889
The optimization of tertiary carbinamine derived inhibitors of BACE1 from its discovery as an unstable lead to low nanomolar cell active compounds is described. Five-membered heterocycles are reported as stable and potency enhancing linkers. In the course of this work, we have discovered a clear trend where the activity of inhibitors at a given assay pH is dependent on pKa of the amino group that interacts directly with the catalytic aspartates. The potency of compounds as inhibitors of Αβ production in a cell culture assay correlated much better with BACE1 enzyme potency measured at pH 7.5 than at pH 4.5. 相似文献
64.
Thomas M. Bridges J. Phillip Kennedy Meredith J. Noetzel Micah L. Breininger Patrick R. Gentry P.J. Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(6):1972-1975
This Letter describes a chemical lead optimization campaign directed at VU0119498, a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) with the goal of developing a selective M1 PAM. An iterative library synthesis approach delivered a potent (M1 EC50 = 830 nM) and highly selective M1 PAM (>30 μM vs M2–M5). 相似文献
65.
Thomas M. Bridges J. Phillip Kennedy Corey R. Hopkins P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(19):5617-5622
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative parallel synthesis approach was employed to incorporate basic heterocycles to improve physiochemical properties. 相似文献
66.
Thomas M. Bridges J. Phillip Kennedy Hyekyung P. Cho Micah L. Breininger Patrick R. Gentry Corey R. Hopkins P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(2):558-562
This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M5-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan Gq mAChR M1, M3, M5 PAM. An iterative library synthesis approach delivered the first selective M5 PAM (no activity at M1–M4 @ 30 μM), and an important tool compound to study the role of M5 in the CNS. 相似文献
67.
In vivo cytometry: a spectrum of possibilities. 总被引:1,自引:0,他引:1
Alice Chung Scott Karlan Erik Lindsley Sebastian Wachsmann-Hogiu Daniel L Farkas 《Cytometry. Part A》2006,69(3):142-146
BACKGROUND: We investigate whether optical imaging can reliably detect abnormalities in tissue, in a range of specimens (live cells in vitro; fixed, fresh ex-vivo and in vivo tissue), without the use of added contrast agents, and review our promising spectral methods for achieving quantitative, real-time, high resolution intrasurgical optical diagnostics. METHODS: We use reflectance, fluorescence, two-photon, and Mie scattering imaging, performed with instrumentation we developed or modified, to detect intrinsic tissue signatures. Emphasis is on spectral/hyperspectral imaging approaches allowing the equivalent of in vivo pathology. RESULTS: With experimental focus on unstained specimens, we demonstrate the ability to segment tissue images for cancer detection. Spectral reflectance imaging, coupled with advanced analysis, typically yields 90% specificity and sensitivity. Autofluorescence is also shown to be diagnostically useful, with lymph nodes results highlighted here. Elastic scattering hyperspectral imaging endoscopy, using a new instrument we designed and built, shows promise in bronchoscopic detection of dysplasia and early cancer in patients. CONCLUSIONS: The results demonstrate that advanced optical imaging can detect and localize cellular signatures of cancer in real-time, in vivo, without the use of contrast agents, in animals and humans. This is an important step towards tight spatio-temporal coupling between such detection and clinical intervention. 相似文献
68.
Nicole R. Miller R. Nathan Daniels David Lee P. Jeffrey Conn Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2010,20(7):2174-2177
This Letter describes the synthesis and SAR, developed through an iterative analog library approach, of a novel series of selective M1 mAChR antagonists, based on an N-(4-(4-alkylpiperazin-1-yl)phenyl)benzamide scaffold for the potential treatment of Parkinson’s disease, dystonia and other movement disorders. Compounds in this series possess M1 antagonist IC50s in the 350 nM to >10 μM range with varying degrees of functional selectivity versus M2–M5. 相似文献
69.
Drosophila melanogaster is a widely used model organism for genetic dissection of developmental processes. To exploit its full potential for studying the genetic basis of male fertility, we performed a large-scale screen for male-sterile (ms) mutations. From a collection of 12,326 strains carrying ethyl-methanesulfonate-treated, homozygous viable second or third chromosomes, 2216 ms lines were identified, constituting the largest collection of ms mutations described to date for any organism. Over 2000 lines were cytologically characterized and, of these, 81% failed during spermatogenesis while 19% manifested postspermatogenic processes. Of the phenotypic categories used to classify the mutants, the largest groups were those that showed visible defects in meiotic chromosome segregation or cytokinesis and those that failed in sperm individualization. We also identified 62 fertile or subfertile lines that showed high levels of chromosome loss due to abnormal mitotic or meiotic chromosome transmission in the male germ line or due to paternal chromosome loss in the early embryo. We argue that the majority of autosomal genes that function in male fertility in Drosophila are represented by one or more alleles in the ms collection. Given the conservation of molecular mechanisms underlying important cellular processes, analysis of these mutations should provide insight into the genetic networks that control male fertility in Drosophila and other organisms, including humans. 相似文献
70.
Cutting edge: BLyS enables survival of transitional and mature B cells through distinct mediators 总被引:20,自引:0,他引:20
Hsu BL Harless SM Lindsley RC Hilbert DM Cancro MP 《Journal of immunology (Baltimore, Md. : 1950)》2002,168(12):5993-5996
These studies characterize BLyS responsiveness and receptor expression among transitional and mature peripheral B cells. The results show a maturation-associated increase in BLyS binding capacity that reflects differential expression patterns of the three BLyS receptors. Accordingly, BLyS administration enlarges only late transitional and mature peripheral B (MB) cell compartments. Furthermore, bromodeoxyuridine labeling and cell cycle analyses show these effects are mediated through enhanced proportional survival of cells traversing the T2, T3, and MB cell stages, rather than by causing proliferation or slowing transit within these subsets. Despite similar effects on survival, BLyS up-regulates the antiapoptotic genes A1 and bcl-x(L) in MB cells but not immature B cells. Together, these findings show that, while BLyS influences B cell survival in several peripheral differentiation subsets, the downstream mediators differ, thus providing the first direct evidence for an established B lineage survival system whose intermediates change as B cells mature. 相似文献