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991.
Smallheer JM Alexander RS Wang J Wang S Nakajima S Rossi KA Smallwood A Barbera F Burdick D Luettgen JM Knabb RM Wexler RR Jadhav PK 《Bioorganic & medicinal chemistry letters》2004,14(21):5263-5267
Modifications to the P4 moiety and pyrazole C3 substituent of factor Xa inhibitor SN-429 provided several new compounds, which are 5-10nM inhibitors of factor IXa. An X-ray crystal structure of one example complexed to factor IXa shows that these compounds adopt a similar binding mode to that previously observed with pyrazole inhibitors in the factor Xa active site both with regard to how the inhibitor binds and the position of Tyr99. 相似文献
992.
Sutton JC Bolton SA Davis ME Hartl KS Jacobson B Mathur A Ogletree ML Slusarchyk WA Zahler R Seiler SM Bisacchi GS 《Bioorganic & medicinal chemistry letters》2004,14(9):2233-2239
A series of nonguanidine N1-activated C4-carboxy azetidinone tryptase inhibitors was prepared by solid-phase methodology to quickly assess the SAR associated with distal functionality on the N1-activating group. From these studies, potent inhibitors with improved specificity were discovered. 相似文献
993.
Zhang YM Cockerill S Guntrip SB Rusnak D Smith K Vanderwall D Wood E Lackey K 《Bioorganic & medicinal chemistry letters》2004,14(1):111-114
A series of 6-alkoxy-4-anilinoquinazoline compounds was prepared and evaluated for in vitro inhibition of the erbB2 and EGFR kinase activity. The IC(50) values of the best compounds were below 0.10 uM. Further, several of these compounds inhibit the growth of erbB2 and EGFR over-expressing tumor cell lines at concentrations below 1 uM. 相似文献
994.
Lowe DB Magnuson S Qi N Campbell AM Cook J Hong Z Wang M Rodriguez M Achebe F Kluender H Wong WC Bullock WH Salhanick AI Witman-Jones T Bowling ME Keiper C Clairmont KB 《Bioorganic & medicinal chemistry letters》2004,14(12):3155-3159
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes. 相似文献
995.
Watkins WJ Lemoine RC Chong L Cho A Renau TE Kuo B Wong V Ludwikow M Garizi N Iqbal N Barnard J Jankowska R Singh R Madsen D Lolans K Lomovskaya O Oza U Dudley MN 《Bioorganic & medicinal chemistry letters》2004,14(20):5133-5137
Structure-activity relationships of a novel series of fungal efflux pump inhibitors with respect to potentiation of the activity of fluconazole against strains of Candida albicans and Candida glabrata over-expressing ABC-type efflux pumps are systematically explored. 相似文献
996.
Heasley BH Jarosz R Carter KM Van SJ Lynch KR Macdonald TL 《Bioorganic & medicinal chemistry letters》2004,14(15):4069-4074
A recently reported dual LPA(1)/LPA(3) receptor antagonist (1) has been modified so as to modulate the basicity, sterics, and dipole moment of the 2-pyridyl moiety. Additionally, the implications of installing nonhydrolyzable phosphate head group isosteres with regard to antagonist potency and selectivity at LPA receptors is described. This study has resulted in the development of the first nonhydrolyzable and presumably phosphatase-resistant LPA(3)-selective antagonist reported to date. 相似文献
997.
Potentiation of cytotoxic drug activity in human tumour cell lines, by amine-substituted 2-arylbenzimidazole-4-carboxamide PARP-1 inhibitors 总被引:3,自引:0,他引:3
White AW Curtin NJ Eastman BW Golding BT Hostomsky Z Kyle S Li J Maegley KA Skalitzky DJ Webber SE Yu XH Griffin RJ 《Bioorganic & medicinal chemistry letters》2004,14(10):2433-2437
The synthesis and biological evaluation of a new series of amine-substituted 2-arylbenzimidazole-4-carboxamide inhibitors of the DNA-repair enzyme poly(ADP-ribose) polymerase-1 (PARP-1) is reported. The introduction of an amine substituent at the 2-aryl position is not detrimental to activity, with most inhibitors exhibiting K(i) values for PARP-1 inhibition in the low nanomolar range. Two compounds in this series were found to potentiate the cytotoxicity of the DNA-methylating agent temozolomide by 4-5-fold in a human colorectal cancer cell line. 相似文献
998.
999.
The unresolved mechanism by which a single strand of DNA recognizes homology in duplex DNA is central to understanding genetic recombination and repair of double-strand breaks. Using stopped-flow fluorescence we monitored strand exchange catalyzed by E. coli RecA protein, measuring simultaneously the rate of exchange of A:T base pairs and the rates of formation and dissociation of the three-stranded intermediates called synaptic complexes. The rate of exchange of A:T base pairs was indistinguishable from the rate of formation of synaptic complexes, whereas the rate of displacement of a single strand from complexes was five to ten times slower. This physical evidence shows that a subset of bases exchanges at a rate that is fast enough to account for recognition of homology. Together, several studies suggest that a mechanism governed by the dynamic structure of DNA and catalyzed by diverse enzymes underlies both recognition of homology and initiation of strand exchange. 相似文献
1000.
Luo Z Palasis M Yamakawa M Liu LX Vincent KA Trudell L Akita GA Koch WJ Cheng SH Gregory RJ Jiang C 《The journal of gene medicine》2004,6(10):1061-1068
BACKGROUND: Previous studies have shown that incubation of balloon-injured rat carotid arteries with adenoviral vectors encoding the carboxyl terminus of the beta-adrenergic receptor kinase (Ad2/betaARKct) for 30 min reduces neointima formation. However, it is unclear whether this beneficial effect of betaARKct could be achieved using a catheter-based vector delivery system and whether the observed inhibition of neointima formation translated into a reduction of vessel stenosis. METHODS: In this study, Ad2/betaARKct was infused into the balloon-injured site of rabbit iliac arteries using a porous infusion catheter over 2 min. Twenty-eight days after gene transfer, angiographic and histological assessments were performed. RESULTS: Angiographic and histological assessments indicate significant (p < 0.05) inhibition of iliac artery neointima formation and lumen stenosis by Ad2/betaARKct. Our studies demonstrate that an inhibitory effect of Ad2/betaARKct on neointima formation is achievable using a catheter-based vector delivery system and that the inhibition of neointima formation translates into a gain in the vessel minimal luminal diameter. The extent of inhibition (35%) was comparable to that observed with adenoviral-mediated expression of thymidine kinase plus ganciclovir treatment, a cytotoxic gene therapy approach for restenosis. CONCLUSIONS: These results suggest that adenoviral-mediated gene transfer of betaARKct is a clinically viable cytostatic gene therapy strategy for the treatment of restenosis. 相似文献