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51.
W J Greenlee E D Thorsett J P Springer A A Patchett E H Ulm T C Vassil 《Biochemical and biophysical research communications》1984,122(2):791-797
A class of potent inhibitors of angiotensin-converting enzyme (dipeptidyl carboxypeptidase, E.C. 3.4.15.1) is reported, in which an alpha-aza substitution into the substituted N-carboxymethyl dipeptide structure of enalapril is made. The inhibitors 2 exhibit striking alterations in their conformational and acid-base properties due to the aza substitution, as is clear from pKa data and the x-ray crystal structure of a model azapeptide. In spite of this, they bind tightly to the enzyme, with inhibitor potency comparable to that of captopril. 相似文献
52.
T.K. Sasikumar Li Qiang Duane A. Burnett William J. Greenlee Cheng Li Mariagrazia Grilli Rosalia Bertorelli Gianluca Lozza Angelo Reggiani 《Bioorganic & medicinal chemistry letters》2010,20(8):2474-2477
A-ring modifications on the triazafluorenone core structure were investigated. Five membered heterocycles such as pyrazoles and isothiazoles are not tolerated. It has been found that the pyrimidine nucleus was very well tolerated on the left hand side. Amino pyrimidine compounds 24 and 27 showed acceptable PK profile with significant brain penetration. Compound 9 served as a versatile intermediate for a number of chemical transformations. 相似文献
53.
Li Qiang T.K. Sasikumar Duane A. Burnett Jing Su Haiqun Tang Yuanzan Ye Robert D. Mazzola Zhaoning Zhu Brian A. McKittrick William J. Greenlee Ahmad Fawzi Michelle Smith Hongtao Zhang Jean E. Lachowicz 《Bioorganic & medicinal chemistry letters》2010,20(3):836-840
A series of novel dopamine D1 antagonists derived from functionalization of the D-ring of SCH 39166 were prepared. A number of these compounds displayed subnanomolar D1 activity and more than 1000-fold selectivity over D2. We found C-3 derivatization afforded compounds with superior overall profile in comparison to the C-2 and C-4 derivatization. A number of highly potent D1 antagonists were discovered which have excellent selectivity over other dopamine receptors and improved PK profile compared to SCH 39166. 相似文献
54.
T.K. Sasikumar Duane A. Burnett William J. Greenlee Michelle Smith Ahmad Fawzi Hongtao Zhang Jean E. Lachowicz 《Bioorganic & medicinal chemistry letters》2010,20(3):832-835
A series of novel benzazepine derived dopamine D1 antagonists have been discovered. These compounds are highly potent at D1 and showed excellent selectivity over D2 and D4 receptors. SAR studies revealed that a variety of functional groups are tolerated on the D-ring of known tetracyclic benzazepine analog 2, SCH 39166, leading to compounds with nanomolar potency at D1 and good selectivity over D2-like receptors. 相似文献
55.
C Allard V Desgagné J Patenaude M Lacroix L Guillemette MC Battista M Doyon J Ménard JL Ardilouze P Perron L Bouchard MF Hivert 《Epigenetics》2015,10(4):342-351
Leptin is an adipokine that acts in the central nervous system and regulates energy balance. Animal models and human observational studies have suggested that leptin surge in the perinatal period has a critical role in programming long-term risk of obesity. In utero exposure to maternal hyperglycemia has been associated with increased risk of obesity later in life. Epigenetic mechanisms are suspected to be involved in fetal programming of long term metabolic diseases. We investigated whether DNA methylation levels near LEP locus mediate the relation between maternal glycemia and neonatal leptin levels using the 2-step epigenetic Mendelian randomization approach. We used data and samples from up to 485 mother-child dyads from Gen3G, a large prospective population-based cohort. First, we built a genetic risk score to capture maternal glycemia based on 10 known glycemic genetic variants (GRS10) and showed it was an adequate instrumental variable (β = 0.046 mmol/L of maternal fasting glucose per additional risk allele; SE = 0.007; P = 7.8 × 10−11; N = 467). A higher GRS10 was associated with lower methylation levels at cg12083122 located near LEP (β = −0.072 unit per additional risk allele; SE = 0.04; P = 0.05; N = 166). Direction and effect size of association between the instrumental variable GRS10 and methylation at cg12083122 were consistent with the negative association we observed using measured maternal glycemia. Lower DNA methylation levels at cg12083122 were associated with higher cord blood leptin levels (β = −0.17 log of cord blood leptin per unit; SE = 0.07; P = 0.01; N = 170). Our study supports that maternal glycemia is part of causal pathways influencing offspring leptin epigenetic regulation. 相似文献
56.
Cumming JN Smith EM Wang L Misiaszek J Durkin J Pan J Iserloh U Wu Y Zhu Z Strickland C Voigt J Chen X Kennedy ME Kuvelkar R Hyde LA Cox K Favreau L Czarniecki MF Greenlee WJ McKittrick BA Parker EM Stamford AW 《Bioorganic & medicinal chemistry letters》2012,22(7):2444-2449
From an initial lead 1, a structure-based design approach led to identification of a novel, high-affinity iminohydantoin BACE1 inhibitor that lowers CNS-derived Aβ following oral administration to rats. Herein we report SAR development in the S3 and F' subsites of BACE1 for this series, the synthetic approaches employed in this effort, and in vivo data for the optimized compound. 相似文献
57.
Wu WL Burnett DA Spring R Qiang L Sasikumar TK Domalski MS Greenlee WJ O'Neill K Hawes BE 《Bioorganic & medicinal chemistry letters》2006,16(14):3668-3673
Isosteric replacement of the urea group of lead compound 1 led to novel substituted piperidine phenylamide analogues. SAR on the electron-induced effects of various linkers as well as substituents on the phenyl rings and the piperidine nitrogen has been investigated. Many single-digit nanomolar MCH R1 antagonists have been identified from this series. 相似文献
58.
Parker DL Meng D Ratcliffe RW Wilkening RR Sperbeck DM Greenlee ML Colwell LF Lambert S Birzin ET Frisch K Rohrer SP Nilsson S Thorsell AG Hammond ML 《Bioorganic & medicinal chemistry letters》2006,16(17):4652-4656
Several tetrahydrofluorenones with a triazole fused across C7-C8 showed high levels of ERbeta-selectivity and were found to be potent ERbeta-agonists. As a class they demonstrate improved oral bioavailability in the rat over a parent class of 7-hydroxy-tetrahydrofluorenones. The most selective agonist displayed 5.7 nM affinity and 333-fold selectivity for ERbeta. 相似文献
59.
Jack D. Scott Michael W. Miller Sarah W. Li Sue-Ing Lin Henry A. Vaccaro Liwu Hong Deborra E. Mullins Mario Guzzi Jay Weinstein Robert A. Hodgson Geoffrey B. Varty Andrew W. Stamford Tin-Yau Chan Brian A. McKittrick William J. Greenlee Tony Priestley Eric M. Parker 《Bioorganic & medicinal chemistry letters》2009,19(21):6018-6022
Vasopressin 1b (V1b) antagonists have been postulated as possible treatments for depression and anxiety. A novel series of potent and selective V1b antagonists has been identified starting from an in-house screen hit. The incorporation of a sulfonamide linker between a tetrahydroisoquinoline core and amino piperidine lead to the identification of a V1b antagonist with similar affinity for human and rat receptors. Further optimization of the right hand portion afforded potent V1b antagonists that possessed moderate to high selectivity over other receptors. 相似文献
60.