全文获取类型
收费全文 | 187篇 |
免费 | 24篇 |
出版年
2023年 | 1篇 |
2022年 | 1篇 |
2020年 | 2篇 |
2019年 | 5篇 |
2018年 | 5篇 |
2017年 | 10篇 |
2016年 | 3篇 |
2015年 | 3篇 |
2014年 | 3篇 |
2013年 | 21篇 |
2012年 | 17篇 |
2011年 | 14篇 |
2010年 | 13篇 |
2009年 | 12篇 |
2008年 | 14篇 |
2007年 | 3篇 |
2006年 | 7篇 |
2005年 | 8篇 |
2004年 | 6篇 |
2003年 | 4篇 |
2002年 | 3篇 |
2001年 | 4篇 |
2000年 | 1篇 |
1999年 | 4篇 |
1998年 | 1篇 |
1994年 | 2篇 |
1992年 | 2篇 |
1991年 | 1篇 |
1990年 | 3篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1984年 | 1篇 |
1981年 | 2篇 |
1979年 | 1篇 |
1977年 | 3篇 |
1974年 | 3篇 |
1972年 | 1篇 |
1968年 | 1篇 |
1967年 | 1篇 |
1965年 | 1篇 |
1963年 | 1篇 |
1961年 | 3篇 |
1960年 | 3篇 |
1959年 | 2篇 |
1958年 | 4篇 |
1956年 | 1篇 |
1955年 | 1篇 |
1939年 | 1篇 |
排序方式: 共有211条查询结果,搜索用时 187 毫秒
101.
Mark Turlington Aspen Chun Sakshi Tomar Aimee Eggler Valerie Grum-Tokars Jon Jacobs J. Scott Daniels Eric Dawson Adrian Saldanha Peter Chase Yahira M. Baez-Santos Craig W. Lindsley Peter Hodder Andrew D. Mesecar Shaun R. Stauffer 《Bioorganic & medicinal chemistry letters》2013,23(22):6172-6177
Herein we report the discovery and SAR of a novel series of SARS-CoV 3CLpro inhibitors identified through the NIH Molecular Libraries Probe Production Centers Network (MLPCN). In addition to ML188, ML300 represents the second probe declared for 3CLpro from this collaborative effort. The X-ray structure of SARS-CoV 3CLpro bound with a ML300 analog highlights a unique induced-fit reorganization of the S2–S4 binding pockets leading to the first sub-micromolar noncovalent 3CLpro inhibitors retaining a single amide bond. 相似文献
102.
Kimberly M. Lovell Andrew S. Felts Alice L. Rodriguez Daryl F. Venable Hyekyung P. Cho Ryan D. Morrison Frank W. Byers J. Scott Daniels Colleen M. Niswender P. Jeffrey Conn Craig W. Lindsley Kyle A. Emmitte 《Bioorganic & medicinal chemistry letters》2013,23(13):3713-3718
Development of SAR in an N-acyl-N′-arylpiperazine series of negative allosteric modulators of mGlu1 using a functional cell-based assay is described in this Letter. Characterization of selected compounds in protein binding assays was used to aid in selecting VU0469650 for further profiling in ancillary pharmacology assays and pharmacokinetic studies. VU0469650 demonstrated an excellent selectivity profile and good exposure in both plasma and brain samples following intraperitoneal dosing in rats. 相似文献
103.
Patrick R. Gentry Thomas M. Bridges Atin Lamsal Paige N. Vinson Emery Smith Peter Chase Peter S. Hodder Julie L. Engers Colleen M. Niswender J. Scott Daniels P. Jeffrey Conn Michael R. Wood Craig W. Lindsley 《Bioorganic & medicinal chemistry letters》2013,23(10):2996-3000
This Letter describes the further chemical optimization of the M5 PAM MLPCN probes ML129 and ML172. A multi-dimensional iterative parallel synthesis effort quickly explored isatin replacements and a number of southern heterobiaryl variations with no improvement over ML129 and ML172. An HTS campaign identified several weak M5 PAMs (M5 EC50 >10 μM) with a structurally related isatin core that possessed a southern phenethyl ether linkage. While SAR within the HTS series was very shallow and unable to be optimized, grafting the phenethyl ether linkage onto the ML129/ML172 cores led to the first sub-micromolar M5 PAM, ML326 (VU0467903), (human and rat M5 EC50s of 409 nM and 500 nM, respectively) with excellent mAChR selectivity (M1–M4 EC50s >30 μM) and a robust 20-fold leftward shift of the ACh CRC. 相似文献
104.
Reid PR Bridges TM Sheffler DJ Cho HP Lewis LM Days E Daniels JS Jones CK Niswender CM Weaver CD Conn PJ Lindsley CW Wood MR 《Bioorganic & medicinal chemistry letters》2011,21(9):2697-2701
This Letter describes a chemical lead optimization campaign directed at VU0108370, a weak M1 PAM hit with a novel chemical scaffold from a functional HTS screen within the MLPCN. An iterative parallel synthesis approach rapidly established SAR for this series and afforded VU0405652 (ML169), a potent, selective and brain penetrant M1 PAM with an in vitro profile comparable to the prototypical M1 PAM, BQCA, but with an improved brain to plasma ratio. 相似文献
105.
Lamb JP Engers DW Niswender CM Rodriguez AL Venable DF Conn PJ Lindsley CW 《Bioorganic & medicinal chemistry letters》2011,21(9):2711-2714
This Letter describes a chemical lead optimization campaign directed at a weak mGlu5 NAM discovered while developing SAR for the mGlu5 PAM, ADX-47273. An iterative parallel synthesis effort discovered multiple, subtle molecular switches that afford potent mGlu5 NAMs, mGlu5 PAMs as well as mGlu5 partial antagonists. 相似文献
106.
Nitric oxide (NO) has been implicated in the pathogenesis of renal hemodynamic changes in diabetes mellitus (DM). However, the role of NO in the pathophysiology of diabetic nephropathy remains controversial. Renal hemodynamic changes in experimental DM can be acutely normalized by selective inhibition of neuronal NO synthase (nNOS). This observation suggests a nephroprotective potential of nNOS inhibition in DM. To explore this issue we assessed the long-term effects (12 weeks) of selective nNOS inhibition with the specific inhibitor S-methyl-L-thiocitrulline (SMTC) in uninephrectomized control and streptozotocin-diabetic rats. No beneficial effects of SMTC were observed in nondiabetic controls. In contrast, SMTC delayed the development of proteinuria (32+/-8 vs. 53+/-9 mg/24h, week 8, p < 0.05) and glomerulosclerosis (GS, 0.30+/-0.08 vs. 0.57+/-0.05, p < 0.05) in diabetic rats. These effects coincided with early effects of treatment on the glomerular filtration rate, and were associated with lower renal expression of nNOS. Furthermore, SMTC-treated diabetic rats demonstrated reduced weight gain and urinary sodium excretion as compared to vehicle-treated counterparts, despite similar metabolic control and blood pressure. In summary, long-term nNOS inhibition had modest nephroprotective effects in uninephrectomized diabetic rats. These effects may be mediated by renal hemodynamic mechanisms, as well as by lower food (protein) intake. 相似文献
107.
BRCA1 C-terminal (BRCT) domains are integral signaling modules in the DNA damage response (DDR). Aside from their established roles as phospho-peptide binding modules, BRCT domains have been implicated in phosphorylation-independent protein interactions, DNA binding and poly(ADP-ribose) (PAR) binding. These numerous functions can be attributed to the diversity in BRCT domain structure and architecture, where domains can exist as isolated single domains or assemble into higher order homo- or hetero-domain complexes. In this review, we incorporate recent structural and biochemical studies to demonstrate how structural features allow single and tandem BRCT domains to attain a high degree of functional diversity.Key words: BRCT domain, DNA repair, phosphorylation, phospho-peptide interaction, protein interaction, DNA binding, DNA damage response 相似文献
108.
Lakdawala SS Lamirande EW Suguitan AL Wang W Santos CP Vogel L Matsuoka Y Lindsley WG Jin H Subbarao K 《PLoS pathogens》2011,7(12):e1002443
The epidemiological success of pandemic and epidemic influenza A viruses relies on the ability to transmit efficiently from person-to-person via respiratory droplets. Respiratory droplet (RD) transmission of influenza viruses requires efficient replication and release of infectious influenza particles into the air. The 2009 pandemic H1N1 (pH1N1) virus originated by reassortment of a North American triple reassortant swine (TRS) virus with a Eurasian swine virus that contributed the neuraminidase (NA) and M gene segments. Both the TRS and Eurasian swine viruses caused sporadic infections in humans, but failed to spread from person-to-person, unlike the pH1N1 virus. We evaluated the pH1N1 and its precursor viruses in a ferret model to determine the contribution of different viral gene segments on the release of influenza virus particles into the air and on the transmissibility of the pH1N1 virus. We found that the Eurasian-origin gene segments contributed to efficient RD transmission of the pH1N1 virus likely by modulating the release of influenza viral RNA-containing particles into the air. All viruses replicated well in the upper respiratory tract of infected ferrets, suggesting that factors other than viral replication are important for the release of influenza virus particles and transmission. Our studies demonstrate that the release of influenza viral RNA-containing particles into the air correlates with increased NA activity. Additionally, the pleomorphic phenotype of the pH1N1 virus is dependent upon the Eurasian-origin gene segments, suggesting a link between transmission and virus morphology. We have demonstrated that the viruses are released into exhaled air to varying degrees and a constellation of genes influences the transmissibility of the pH1N1 virus. 相似文献
109.
Alice L. Rodriguez Ya Zhou Richard Williams C. David Weaver Paige N. Vinson Eric S. Dawson Thomas Steckler Hilde Lavreysen Claire Mackie José M. Bartolomé Gregor J. Macdonald J. Scott Daniels Colleen M. Niswender Carrie K. Jones P. Jeffrey Conn Craig W. Lindsley Shaun R. Stauffer 《Bioorganic & medicinal chemistry letters》2012,22(24):7388-7392
Herein we report the discovery and SAR of a novel series of non-MPEP site metabotropic glutamate receptor 5 (mGlu5) positive allosteric modulators (PAMs) based on an aryl glycine sulfonamide scaffold. This series represents a rare non-MPEP site mGlu5 PAM chemotype. 相似文献
110.
Mueller R Dawson ES Niswender CM Butkiewicz M Hopkins CR Weaver CD Lindsley CW Conn PJ Meiler J 《Journal of molecular modeling》2012,18(9):4437-4446
Activation of metabotropic glutamate receptor subtype 4 has been shown to be efficacious in rodent models of Parkinson's disease. Artificial neural networks were trained based on a recently reported high throughput screen which identified 434 positive allosteric modulators of metabotropic glutamate receptor subtype 4 out of a set of approximately 155,000 compounds. A jury system containing three artificial neural networks achieved a theoretical enrichment of 15.4 when selecting the top 2?% compounds of an independent test dataset. The model was used to screen an external commercial database of approximately 450,000 drug-like compounds. 1,100 predicted active small molecules were tested experimentally using two distinct assays of mGlu(4) activity. This experiment yielded 67 positive allosteric modulators of metabotropic glutamate receptor subtype 4 that confirmed in both experimental systems. Compared to the 0.3?% active compounds in the primary screen, this constituted an enrichment of 22 fold. 相似文献