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41.
Fereshteh Shiri Maryam Salahinejad Rahmatollah Dijoor Massoud Nejati-Yazdinejad 《Journal of receptor and signal transduction research》2018,38(2):151-165
Pathogenic Gram-negative bacteria are responsible for nearly half of the serious human infections. Hologram quantitative structure–activity relationships (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) were implemented on a group of 32 of potent Gram-negative LpxC inhibitors. The most effective HQSAR model was obtained using atoms, bonds, donor, and acceptor as fragment distinction. The cross-validated correlation coefficient (q2), non-cross-validated correlation coefficient (r2), and predictive correlation coefficient (r2Pred) for test set of HQSAR model were 0.937, 0.993, and 0.892, respectively. The generated models were found to be statistically significant as the CoMFA model had (r2?=?0.967, q2?=?0.804, r2Pred?=?0.827); the CoMSIA model had (r2?=?0.963, q2?=?0.752, r2Pred?=?0.857). Molecular docking was employed to validate the results of the HQSAR, CoMFA, and CoMSIA models. Based on the obtained information, six new LpxC inhibitors have been designed. 相似文献
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Qiao JX Cheney DL Alexander RS Smallwood AM King SR He K Rendina AR Luettgen JM Knabb RM Wexler RR Lam PY 《Bioorganic & medicinal chemistry letters》2008,18(14):4118-4123
Ortho-substituted biphenyl moieties are widely used in drug design. We herein report a successful use of the perpendicular conformation of the alpha-substituted phenylcyclopropyl groups to mimic the aplanar, biologically active conformation of the ortho-substituted biphenyl moieties to achieve structural diversity. This is exemplified by the design and synthesis of a series of highly potent pyrazole bicyclic-based Factor Xa (FXa) inhibitors bearing alpha-substituted phenylcyclopropyl P4 moieties. The designed perpendicular conformation was confirmed by the X-ray structure of FXa-bound compound 2r. The potential structural basis for the high FXa potency in the phenylcyclopropyl P4 analogs and their improved FXa inhibitory activities compared with the biphenyl P4 counterparts are discussed. 相似文献
45.
Varnes JG Wacker DA Pinto DJ Orwat MJ Theroff JP Wells B Galemo RA Luettgen JM Knabb RM Bai S He K Lam PY Wexler RR 《Bioorganic & medicinal chemistry letters》2008,18(2):749-754
Efforts to further optimize the clinical candidate razaxaban have led to a new series of pyrazole-based factor Xa (fXa) inhibitors. Designed to prevent the potential formation of primary aniline metabolites in vivo, the nitrogen of the carboxamido linker between the pyrazole and proximal phenyl moiety of the razaxaban scaffold was replaced with a methylene group. The resulting ketones demonstrated excellent potency and selectivity for fXa but initially had poor oral bioavailability. Optimization by conversion from a P1 aminobenzisoxazole to a P1 p-methoxyphenyl residue, replacing the 3-trifluoromethylpyrazole with a 3-amidopyrazole, and employing a pyridone P4 group provided a fXa inhibitor with a potency and pharmacokinetic profile equivalent to that of razaxaban and improved selectivity over thrombin. 相似文献
46.
Smallheer JM Wang S Laws ML Nakajima S Hu Z Han W Jacobson I Luettgen JM Rossi KA Rendina AR Knabb RM Wexler RR Lam PY Quan ML 《Bioorganic & medicinal chemistry letters》2008,18(7):2428-2433
As part of an effort to identify novel backups for previously reported pyrazole-based coagulation Factor Xa inhibitors, the pyrazole 5-carboxamide moiety was replaced by 3-(sulfonylamino)-2-piperidone. This led to the identification of a structurally diverse chemotype that was further optimized to incorporate neutral or weakly basic aryl and heteroaryl P1 groups while maintaining good potency versus Factor Xa. Substitution at the sulfonamide nitrogen provided further improvements in potency and as did introduction of alternate P4 moieties. 相似文献
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Jennifer X. Qiao Sarah R. King Kan He Pancras C. Wong Alan R. Rendina Joseph M. Luettgen Baomin Xin Robert M. Knabb Ruth R. Wexler Patrick Y.S. Lam 《Bioorganic & medicinal chemistry letters》2009,19(2):462-468
We previously disclosed a series of highly potent FXa inhibitors bearing α-substituted (CH2NR1R2) phenylcyclopropyl P4 moieties in the pyrazolodihydropyridone core system. Herein, we describe our continuous SAR efforts in this series. Effects of the C-3 substitution of the pyrazolodihydropyridone core and the α-substitution (R group) of the cyclopropyl ring on FXa binding affinity (FXa Ki), human plasma anticoagulant activity (PT EC2×) and permeability are discussed. A set of compounds obtained from optimization of the R group and the C-3 substituent were orally bioavailable in dogs. Furthermore, representative compounds were highly efficacious in the rabbit arterio-venous shunt thrombosis model (EC50s = 29–81 nM). 相似文献
49.
Wityak J Tobin AE Mousa SA Wexler RR Olson RE 《Bioorganic & medicinal chemistry letters》1999,9(2):123-126
Isoxazolinylacetamides bearing a phosphoramidate group alpha- to the carboxylate moiety (3) were prepared and evaluated for in vitro antiplatelet efficacy. They were found to bind GPIIb/IIIa with high affinity and were potent antagonists of ADP mediated platelet aggregation. 相似文献
50.
The interaction of copper(II)–ibuprofenato complex with calf thymus DNA (ct-DNA) has been explored following, UV-visible spectrophotometry, fluorescence measurement, dynamic viscosity measurements, and circular dichroism spectroscopy. In spectrophotometric studies of ct-DNA it was found that [Cu(ibp)2]2 can form a complex with double-helical DNA. The association constant of [Cu(ibp)2]2 with DNA from UV-Vis study was found to be 6.19 × 104 L mol?1. The values of Kf from fluorescence measurement clearly underscore the high affinity of [Cu(ibp)2]2 to DNA. The experimental results showed that the conformational changes in DNA helix induced by [Cu(ibp)2]2 are the reason for the fluorescence quenching of the DNA-Hoechst system. In addition, the fluorescence emission spectra of intercalated methylene blue (MB) with increasing concentrations of [Cu(ibp)2]2 represented a significant increase of MB intensity as to release MB from MB-DNA system. The results of circular dichroism (CD) suggested that copper(II)–ibuprofenato complex can change the conformation of DNA. In addition, the results of viscosity measurements suggest that copper(II)–ibuprofenato complex may bind with non-classical intercalative mode. From spectroscopic and hydrodynamic studies, it has been found that [Cu(ibp)2]2 interacts with DNA by partial intercalation mode which contains intercalation and groove properties. 相似文献