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991.
Xiang MA Rybczynski PJ Patel M Chen RH McComsey DF Zhang HC Gunnet JW Look R Wang Y Minor LK Zhong HM Villani FJ Demarest KT Damiano BP Maryanoff BE 《Bioorganic & medicinal chemistry letters》2007,17(23):6623-6628
We have continued to explore spirobenzazepines as vasopressin receptor antagonists to follow up on RWJ-339489 (2), which had advanced into preclinical development. Further structural modifications were pursued to find a suitable backup compound for human clinical studies. Thus, we identified carboxylic acid derivative 3 (RWJ-676070; JNJ-17158063) as a potent, balanced vasopressin V(1a)/V(2) receptor antagonist with favorable properties for clinical development. Compound 3 is currently undergoing human clinical investigation. 相似文献
992.
Hay BA Abrams B Zumbrunn AY Valentine JJ Warren LC Petras SF Shelly LD Xia A Varghese AH Hawkins JL Van Camp JA Robbins MD Landschulz K Harwood HJ 《Bioorganic & medicinal chemistry letters》2007,17(16):4411-4414
The discovery and efficacy of a series of potent aminopyrrolidineamide-based inhibitors of sterol regulatory element binding protein site-1 protease is described. 相似文献
993.
Zheng QH Gao M Mock BH Wang S Hara T Nazih R Miller MA Receveur TJ Lopshire JC Groh WJ Zipes DP Hutchins GD DeGrado TR 《Bioorganic & medicinal chemistry letters》2007,17(8):2220-2224
The high-affinity choline transporter (CHT1) system is an attractive target for the development of positron emission tomography (PET) biomarkers to probe brain, cardiac, and cancer diseases. An efficient and convenient synthesis of new radiolabeled CHT1 inhibitors [(11)C]hemicholinium-3 and [(18)F]hemicholinium-3 by solid-phase extraction (SPE) technique using a cation-exchange CM Sep-Pak cartridge has been well developed. The preliminary evaluation of both tracers through biodistribution studies in 9L-glioma rats has been performed, and the uptakes in the heart and tumor were observed, while very low brain uptake was seen. 相似文献
994.
Larsen SD Poel TJ Filipski KJ Kohrt JT Pfefferkorn JA Sorenson RJ Tait BD Askew V Dillon L Hanselman JC Lu GH Robertson A Sekerke C Kowala MC Auerbach BJ 《Bioorganic & medicinal chemistry letters》2007,17(20):5567-5572
An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity. 相似文献
995.
Aflatoxins are toxic and carcinogenic polyketides produced by several Aspergillus species that are known to contaminate agricultural commodities, posing a serious threat to animal and human health. Aflatoxin (AF) biosynthesis is almost fully characterized and involves the coordinated expression of approximately 25 genes clustered in a 70-kb DNA region. Aspergillus parasiticus is an economically important and common agent of AF contamination. Naturally occurring nonaflatoxigenic strains of A. parasiticus are rarely found and generally produce O-methylsterigmatocystin (OMST), the immediate precursor of AF. To elucidate the evolutionary forces acting to retain AF and OMST pathway extrolites (chemotypes), we sequenced 21 intergenic regions spanning the entire cluster in 24 A. parasiticus isolates chosen to represent the genetic diversity within a single Georgia field population. Linkage disequilibrium analyses revealed five distinct recombination blocks in the A. parasiticus cluster. Phylogenetic network analyses showed a history of recombination between chemotype-specific haplotypes, as well as evidence of contemporary recombination. We performed coalescent simulations of variation in recombination blocks and found an approximately twofold deeper coalescence for cluster genealogies compared to noncluster genealogies, our internal standard of neutral evolution. Significantly deeper cluster genealogies are indicative of balancing selection in the AF cluster of A. parasiticus and are further corroborated by the existence of trans-species polymorphisms and common haplotypes in the cluster for several closely related species. Estimates of Ka/Ks for representative cluster genes provide evidence of selection for OMST and AF chemotypes, and indicate a possible role of chemotypes in ecological adaptation and speciation. 相似文献
996.
Kendall JD Rewcastle GW Frederick R Mawson C Denny WA Marshall ES Baguley BC Chaussade C Jackson SP Shepherd PR 《Bioorganic & medicinal chemistry》2007,15(24):7677-7687
A series of 2-methyl-5-nitrobenzenesulfonohydrazides were prepared and evaluated as inhibitors of PI3K. An isoquinoline derivative shows good selectivity for the p110α isoform over p110β and p110δ, and also demonstrates good in vitro activity in a cell proliferation assay. Molecular modelling provides a rationalisation for the observed SAR. 相似文献
997.
Fierro A Osorio-Olivares M Cassels BK Edmondson DE Sepúlveda-Boza S Reyes-Parada M 《Bioorganic & medicinal chemistry》2007,15(15):5198-5206
Four enantiomerically pure (S)-4-alkylthioamphetamine derivatives were evaluated as monoamine oxidase (MAO) inhibitors using the human and rat isoforms of the enzyme. Molecular dockings were performed in order to gain insights regarding the binding mode of these inhibitors. All compounds were potent and selective MAO-A inhibitors although different rank orders of potencies were observed against the enzymes from different species. This behavior can be rationalized on the basis of different binding modes to each enzyme, as determined in silico. These findings further support the concept that MAO inhibitory activity of novel compounds, determined with enzymes from diverse mammalian species, should be considered with caution if human MAO is the final target to be addressed. 相似文献
998.
Coordinating terminal differentiation with permanent exit from the cell cycle is crucial for proper organogenesis, yet how the cell cycle is blocked in differentiated tissues remains unclear. Important roles for retinoblastoma family proteins and Cyclin-dependent kinase inhibitors have been delineated, but in many cases it remains unclear what triggers cell cycle exit. This review focuses on describing recent advances in deciphering how terminal differentiation and exit from the cell cycle are coordinated. 相似文献
999.
Progress in computational protein design 总被引:4,自引:3,他引:1
Current progress in computational structure-based protein design is reviewed in the areas of methodology and applications. Foundational advances include new potential functions, more efficient ways of computing energetics, flexible treatments of solvent, and useful energy function approximations, as well as ensemble-based approaches to scoring designs for inclusion of entropic effects, improvements to guaranteed and to stochastic search techniques, and methods to design combinatorial libraries for screening and selection. Applications include new approaches and successes in the design of specificity for protein folding, binding, and catalysis, in the redesign of proteins for enhanced binding affinity, and in the application of design technology to study and alter enzyme catalysis. Computational protein design continues to mature and advance. 相似文献
1000.