全文获取类型
收费全文 | 11092篇 |
免费 | 1103篇 |
国内免费 | 5篇 |
出版年
2023年 | 70篇 |
2022年 | 119篇 |
2021年 | 328篇 |
2020年 | 159篇 |
2019年 | 202篇 |
2018年 | 265篇 |
2017年 | 233篇 |
2016年 | 379篇 |
2015年 | 603篇 |
2014年 | 676篇 |
2013年 | 803篇 |
2012年 | 876篇 |
2011年 | 956篇 |
2010年 | 571篇 |
2009年 | 448篇 |
2008年 | 680篇 |
2007年 | 670篇 |
2006年 | 555篇 |
2005年 | 495篇 |
2004年 | 467篇 |
2003年 | 373篇 |
2002年 | 356篇 |
2001年 | 132篇 |
2000年 | 128篇 |
1999年 | 106篇 |
1998年 | 89篇 |
1997年 | 67篇 |
1996年 | 64篇 |
1995年 | 76篇 |
1994年 | 50篇 |
1993年 | 42篇 |
1992年 | 62篇 |
1991年 | 61篇 |
1990年 | 67篇 |
1989年 | 56篇 |
1988年 | 57篇 |
1987年 | 68篇 |
1986年 | 63篇 |
1985年 | 40篇 |
1984年 | 63篇 |
1983年 | 37篇 |
1982年 | 33篇 |
1981年 | 48篇 |
1980年 | 35篇 |
1979年 | 33篇 |
1978年 | 35篇 |
1977年 | 31篇 |
1976年 | 33篇 |
1975年 | 35篇 |
1972年 | 27篇 |
排序方式: 共有10000条查询结果,搜索用时 46 毫秒
991.
Pierre F Stefan E Nédellec AS Chevrel MC Regan CF Siddiqui-Jain A Macalino D Streiner N Drygin D Haddach M O'Brien SE Anderes K Ryckman DM 《Bioorganic & medicinal chemistry letters》2011,21(22):6687-6692
A novel class of pan-Pim kinase inhibitors was designed by modifying the CK2 inhibitor CX-4945. Introduction of a triazole or secondary amide functionality on the C-7 position and 2'-halogenoanilines on C-5 resulted in potent inhibitors of the Pim-1 and Pim-2 isoforms, with many analogs active at single digit nanomolar concentrations. The molecules inhibited the phosphorylation at Serine 112 of the apoptosis effector BAD, and had potent antiproliferative effects on the AML cell line MV-4-11 (IC(50) <30 nM). This work delivers an excellent lead-optimization platform for Pim targeting anticancer therapies. 相似文献
992.
Gilbert AM Bursavich MG Lombardi S Adedoyin A Dwyer JM Hughes Z Kern JC Khawaja X Rosenzweig-Lipson S Moore WJ Neal SJ Olsen M Rizzo SJ Springer D 《Bioorganic & medicinal chemistry letters》2011,21(1):195-199
A series of 3-(pyridin-2-yl-ethynyl)benzamide negative allosteric modulators of the metabotropic glutamate receptor 5 (mGluR5 NAMs) have been prepared. Starting from HTS hit 1 (IC50: 926 nM), potent mGluR5 NAMs showing excellent potencies (IC50s <50 nM) and good physicochemical profiles were prepared by monitoring LipE values. One compound 26 showed excellent mGluR5 binding (Ki: 21 nM) and antagonism (IC50: 8 nM), an excellent rat PK profile (CL: 12 mL/min/kg, %F: 85) and showed oral activity in a mouse 4-Plate Behavioral model of anxiety (MED: 30 mpk) and a mouse Stress Induced Hyperthermia model of anxiety (MED 17.8 mpk). 相似文献
993.
Hughes AD Chin KH Dunham SL Jasper JR King KE Lee TW Mammen M Martin J Steinfeld T 《Bioorganic & medicinal chemistry letters》2011,21(5):1354-1358
We sought to design dual pharmacology bronchodilators targeting both the M3 muscarinic acetylcholine and beta-2 adrenergic (β2) receptors by applying our multivalent approach to drug discovery. Herein, we describe our initial discovery and the SAR of the first such compounds with matched potencies at both receptors. 相似文献
994.
Ratcliffe P Adam JM Baker J Bursi R Campbell R Clark JK Cottney JE Deehan M Easson AM Ecker D Edwards D Epemolu O Evans L Fields R Francis S Harradine P Jeremiah F Kiyoi T McArthur D Morrison A Passier P Pick J Schnabel PG Schulz J Steinbrede H Walker G Westwood P Wishart G de Haes JU 《Bioorganic & medicinal chemistry letters》2011,21(8):2541-2546
We report an expansion of the structure-activity relationship (SAR) of a novel series of indole-3-heterocyclic CB1 receptor agonists. Starting from the potent but poorly soluble lead, 1, a rational approach was taken in order to balance solubility, hERG activity and potency while retaining the desired long duration of action within the mouse tail flick test. This led to the discovery of compound 38 which successfully progressed into clinical development. 相似文献
995.
Koltun E Richards S Chan V Nachtigall J Du H Noson K Galan A Aay N Hanel A Harrison A Zhang J Won KA Tam D Qian F Wang T Finn P Ogilvie K Rosen J Mohan R Larson C Lamb P Nuss J Kearney P 《Bioorganic & medicinal chemistry letters》2011,21(22):6773-6777
A novel series of potent inhibitors of glucosylceramide synthase are described. The optimization of biochemical and cellular potency as well as ADME properties led to compound 23c. Broad tissue distribution was obtained following oral administration to mice. Thus 23c could be another useful tool compound for studying the effects of GCS inhibition in vitro and in vivo. 相似文献
996.
Tran TD Pryde DC Jones P Adam FM Benson N Bish G Calo F Ciaramella G Dixon R Duckworth J Fox DN Hay DA Hitchin J Horscroft N Howard M Gardner I Jones HM Laxton C Parkinson T Parsons G Proctor K Smith MC Smith N Thomas A 《Bioorganic & medicinal chemistry letters》2011,21(8):2389-2393
The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model. 相似文献
997.
Sun X Qiu J Strong SA Green LS Wasley JW Colagiovanni DB Mutka SC Blonder JP Stout AM Richards JP Chun L Rosenthal GJ 《Bioorganic & medicinal chemistry letters》2011,21(12):3671-3675
S-Nitrosoglutathione reductase (GSNOR) is a member of the alcohol dehydrogenase family (ADH) that regulates the levels of S-nitrosothiols (SNOs) through catabolism of S-nitrosoglutathione (GSNO). GSNO and SNOs are implicated in the pathogenesis of many diseases including those in respiratory, cardiovascular, and gastrointestinal systems. The pyrrole based N6022 was recently identified as a potent, selective, reversible, and efficacious GSNOR inhibitor which is currently undergoing clinical development. We describe here the synthesis and structure-activity relationships (SAR) of novel pyrrole based analogues of N6022 focusing on scaffold modification and propionic acid replacement. We identified equally potent and novel GSNOR inhibitors having pyrrole regioisomers as scaffolds using a structure based approach. 相似文献
998.
Assembly of virus capsids and surface proteins must be regulated to ensure that the resulting complex is an infectious virion. In this review, we examine assembly of virus capsids, focusing on hepatitis B virus and bacteriophage MS2, and formation of glycoproteins in the alphaviruses. These systems are structurally and biochemically well-characterized and are simplest-case paradigms of self-assembly. Published data suggest that capsid and glycoprotein assembly is subject to allosteric regulation, that is regulation at the level of conformational change. The hypothesis that allostery is a common theme in viruses suggests that deregulation of capsid and glycoprotein assembly by small molecule effectors will be an attractive antiviral strategy, as has been demonstrated with hepatitis B virus. 相似文献
999.
1000.
Malladi VL Sobczak AJ Meyer TM Pei D Wnuk SF 《Bioorganic & medicinal chemistry》2011,19(18):5507-5519
LuxS (S-ribosylhomocysteinase) catalyzes the cleavage of the thioether linkage of S-ribosylhomocysteine (SRH) to produce homocysteine and 4,5-dihydroxy-2,3-pentanedione (DPD), the precursor to a small signaling molecule that mediates interspecies bacterial communication called autoinducer 2 (AI-2). Inhibitors of LuxS should interfere with bacterial interspecies communication and potentially provide a novel class of antibacterial agents. In this work, SRH analogues containing substitution of a nitrogen atom for the endocyclic oxygen as well as various deoxyriboses were synthesized and evaluated for LuxS inhibition. Two of the [4-aza]SRH analogues showed modest competitive inhibition (K(I) ~40 μM), while most of the others were inactive. One compound that contains a hemiaminal moiety exhibited time-dependent inhibition, consistent with enzyme-catalyzed ring opening and conversion into a more potent species (K(I)(?)=3.5 μM). The structure-activity relationship of the designed inhibitors highlights the importance of both the homocysteine and ribose moieties for high-affinity binding to LuxS active site. 相似文献