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排序方式: 共有236条查询结果,搜索用时 421 毫秒
71.
Simeon Bowers Anh P. Truong Michael Ye Danielle L. Aubele Jennifer M. Sealy R. Jeffrey Neitz Roy K. Hom Wayman Chan Michael S. Dappen Robert A. Galemmo Andrei W. Konradi Hing L. Sham Yong L. Zhu Paul Beroza George Tonn Heather Zhang Jennifer Hoffman Ruth Motter Marcelle Bergeron 《Bioorganic & medicinal chemistry letters》2013,23(9):2743-2749
Polo-like kinase-2 (Plk-2) is a potential therapeutic target for Parkinson’s disease and this Letter describes the SAR of a series of dihydropteridinone based Plk-2 inhibitors. By optimizing both the N-8 substituent and the biaryl region of the inhibitors we obtained single digit nanomolar compounds such as 37 with excellent selectivity for Plk-2 over Plk-1. When dosed orally in rats, compound 37 demonstrated a 41–45% reduction of pS129-α-synuclein levels in the cerebral cortex. 相似文献
72.
Maurizio Franzini Xiaocong M. Ye Marc Adler Danielle L. Aubele Albert W. Garofalo Shawn Gauby Erich Goldbach Gary D. Probst Kevin P. Quinn Pam Santiago Hing L. Sham Danny Tam Anh Truong Zhao Ren 《Bioorganic & medicinal chemistry letters》2013,23(7):1967-1973
Leucine-rich repeat kinase 2 (LRRK2) has been implicated in the pathogenesis of Parkinson’s disease (PD). Inhibition of LRRK2 kinase activity is a therapeutic approach that may lead to new treatments for PD. Herein we report the discovery of a series of [1,2,4]triazolo[4,3-b]pyridazines that are potent against both wild-type and mutant LRRK2 kinase activity in biochemical assays and show an unprecedented selectivity towards the G2019S mutant. A structural rational for the observed selectivity is proposed. 相似文献
73.
Ying-zi Xu Shendong Yuan Simeon Bowers Roy K. Hom Wayman Chan Hing L. Sham Yong L. Zhu Paul Beroza Hu Pan Eric Brecht Nanhua Yao Julie Lougheed Jiangli Yan Danny Tam Zhao Ren Lany Ruslim Michael P. Bova Dean R. Artis 《Bioorganic & medicinal chemistry letters》2013,23(10):3075-3080
Utilizing a structure based design approach, combined with extensive medicinal chemistry execution, highly selective, potent and novel BACE1 inhibitor 8 (BACE1 Alpha assay IC50 = 8 nM) was made from a weak μM potency hit in an extremely efficient way. The detailed SAR and general design approaches will be discussed. 相似文献
74.
Iyengar RR Lynch JK Mulhern MM Judd AS Freeman JC Gao J Souers AJ Zhao G Wodka D Doug Falls H Brodjian S Dayton BD Reilly RM Swanson S Su Z Martin RL Leitza ST Houseman KA Diaz G Collins CA Sham HL Kym PR 《Bioorganic & medicinal chemistry letters》2007,17(4):874-878
The optimization of potent MCHr1 antagonist 1 with respect to improving its in vitro profile by replacement of the 3,4-methylenedioxy phenyl (piperonyl) moiety led to the discovery of 19, a compound that showed excellent MCHr1 binding and functional potencies in addition to possessing superior hERG separation, CYP3A4 profile, and receptor cross-reactivity profiles. 相似文献
75.
Tao ZF Li G Tong Y Stewart KD Chen Z Bui MH Merta P Park C Kovar P Zhang H Sham HL Rosenberg SH Sowin TJ Lin NH 《Bioorganic & medicinal chemistry letters》2007,17(21):5944-5951
An extensive structure-activity relationship study of the 3-position of a series of tricyclic pyrazole-based Chk1 inhibitors is described. As a result, 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-benzonitriles (4) and 4'-(1,4-dihydro-indeno[1,2-c]pyrazol-3-yl)-pyridine-2'-carbonitriles (29) emerged as new lead series. Compared with the original lead compound 2, these new leads fully retain the biological activity in both enzymatic inhibition and cell-based assays. More importantly, the new leads 4 and 29 exhibit favorable physicochemical properties such as lower molecular weight, lower Clog P, and the absence of a hydroxyl group. Furthermore, structure-activity relationship studies were performed at the 6- and 7-positions of 4, which led to the identification of ideal Chk1 inhibitors 49, 50, 51, and 55. These compounds not only potently inhibit Chk1 in an enzymatic assay but also significantly potentiate the cytotoxicity of DNA-damaging agents in cell-based assays while they show little single agent activity. A cell cycle analysis by FACS confirmed that these Chk1 inhibitors efficiently abrogate the G2/M and S checkpoints induced by DNA-damaging agent. The current work paved the way to the identification of several potent Chk1 inhibitors with good pharmacokinetics that are suitable for in vivo study with oral dosing. 相似文献
76.
Backes BJ Longenecker K Hamilton GL Stewart K Lai C Kopecka H von Geldern TW Madar DJ Pei Z Lubben TH Zinker BA Tian Z Ballaron SJ Stashko MA Mika AK Beno DW Kempf-Grote AJ Black-Schaefer C Sham HL Trevillyan JM 《Bioorganic & medicinal chemistry letters》2007,17(7):2005-2012
A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal. 相似文献
77.
Liu M Wang S Clampit JE Gum RJ Haasch DL Rondinone CM Trevillyan JM Abad-Zapatero C Fry EH Sham HL Liu G 《Bioorganic & medicinal chemistry letters》2007,17(3):668-672
A new series of 4-anilinopyrimidines has been synthesized and evaluated as JNK1 inhibitors. SAR studies led to the discovery of potent JNK1 inhibitors with good enzymatic activity as well as cellular potency represented by compound 2b. Kinase selectivity profile and the crystal structure of 2b are also described. 相似文献
78.
Patel JR Shuai Q Dinges J Winn M Pliushchev M Fung S Monzon K Chiou W Wang J Pan L Wagaw S Engstrom K Kerdesky FA Longenecker K Judge R Qin W Imade HM Stolarik D Beno DW Brune M Chovan LE Sham HL Jacobson P Link JT 《Bioorganic & medicinal chemistry letters》2007,17(3):750-755
A novel class of adamantane ethers 11beta-hydroxysteroid hydrogenase type I inhibitors has been discovered. These compounds have excellent HSD-1 potency and selectivity against HSD-2. The structure-activity relationships, selectivity, metabolism, PK, ex vivo pharmacodynamic data, and an X-ray crystal structure of one of these inhibitors bound to h-HSD-1 are discussed. 相似文献
79.
80.
Curtin ML Florjancic AS Cohen J Gu WZ Frost DJ Muchmore SW Sham HL 《Bioorganic & medicinal chemistry letters》2003,13(7):1367-1371
A series of imidazole-containing biphenyls was prepared and evaluated in vitro for inhibition of FTase and cellular Ras processing. Several of these analogues, such as 21, are potent inhibitors of FTase (<1nM), FTase/GGTase selective (>300-fold) and cellularly active (相似文献