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41.
Guo Z Chen Y Wu D Zhu YF Struthers RS Saunders J Xie Q Chen C 《Bioorganic & medicinal chemistry letters》2003,13(20):3617-3622
The synthesis and SAR studies of thieno[2,3-d]pyrimidine-2,4-diones as human GnRH receptor antagonists to treat reproductive diseases are discussed. It was found that the 2-(2-pyridyl)ethyl group on the 5-aminomethyl functionality of the core structure was a key feature for good receptor binding activity. SAR study of the 6-(4-aminophenyl) group suggests that hydrophobic substituents were preferred. The best compound from this series had binding affinity (K(i)) of 0.4 nM to the human GnRH receptor. 相似文献
42.
Guo Z Zhu YF Tucci FC Gao Y Struthers RS Saunders J Gross TD Xie Q Reinhart GJ Chen C 《Bioorganic & medicinal chemistry letters》2003,13(19):3311-3315
The novel synthesis and SAR studies of 6-methyluracils as human GnRH receptor antagonists are discussed. Introduction of a small methyl substituent at the beta-position from N3 of the uracil improved the GnRH binding potency by 5- to 10-fold. The best compound from the series had binding affinity of 5 nM (K(i)) to the human GnRH receptor. 相似文献
43.
Wilcoxen KM Zhu YF Connors PJ Saunders J Gross TD Gao Y Reinhart GJ Struthers RS Chen C 《Bioorganic & medicinal chemistry letters》2002,12(16):2179-2183
SAR studies of 2-arylimidazolo[1,2-a]pyrimid-5-ones 10a-m, which were derived from initial lead 3a, resulted in the discovery of a series of potent nonpeptide human GnRH receptor antagonists. Compounds with good potency (e.g., 10e, K(i)=7.5 nM) were prepared by introduction of a 2-(2-pyridyl)ethyl at the basic nitrogen and a 3-pentyl ester at the 6-position of the bicyclic core. 相似文献
44.
Zhu YF Struthers RS Connors PJ Gao Y Gross TD Saunders J Wilcoxen K Reinhart GJ Ling N Chen C 《Bioorganic & medicinal chemistry letters》2002,12(3):399-402
Initial SAR studies on 1-aminomethyl-2-aryl-3-cyano-pyrrolo[1,2-a]pyrimid-7-one-6-carboxylates as human GnRH receptor antagonists were discussed. 2-(2-Methylaminoethyl)pyridine was discovered to be a key feature for generating active compounds. The best compound from the series had 25 nM (K(i)) binding affinity to human GnRH receptor. 相似文献
45.
Rowbottom MW Tucci FC Connors PJ Gross TD Zhu YF Guo Z Moorjani M Acevedo O Carter L Sullivan SK Xie Q Fisher A Struthers RS Saunders J Chen C 《Bioorganic & medicinal chemistry letters》2004,14(19):4967-4973
The synthesis of a series of (R)-3-[2-(2-amino)phenethyl]-1-(2,6-difluorobenzyl)-6-methyluracils containing a substituted thiophene or thiazole at C-5 is described. SAR around C-5 of the uracil led to the discovery that a 2-thienyl or (2-phenyl)thiazol-4-yl group is required for optimal receptor binding. The best compound from the series had a binding affinity of 2 nM (K(i)) for the human GnRH receptor. A novel and convenient preparation of N-1-(2,6-difluorobenzyl)-6-methyluracil is also described. 相似文献
46.
Rowbottom MW Tucci FC Zhu YF Guo Z Gross TD Reinhart GJ Xie Q Struthers RS Saunders J Chen C 《Bioorganic & medicinal chemistry letters》2004,14(9):2269-2274
The synthesis of a series of (R)-1-alkyl-3-[2-(2-amino)phenethyl]-5-(2-fluorophenyl)-6-methyluracils is discussed. SAR around N-1 of the uracil was explored, which led to the discovery that an electron-deficient 2,6-disubstituted benzyl group is required for optimal receptor binding. The best compound from the series had binding affinity of 0.7 nM (K(i) for the human GnRH receptor, which was 8-fold better than the 2,6-difluorobenzyl analog. 相似文献
47.
48.
Guo Z Wu D Zhu YF Tucci FC Pontillo J Saunders J Xie Q Struthers RS Chen C 《Bioorganic & medicinal chemistry letters》2005,15(3):693-698
A convenient one-pot synthetic route was developed for the preparation of asymmetric 1,3-dialkyl-1,3,5-triazine-2,4,6-triones from readily available alkyl- or aryl-isocyanates, primary amines and N-chlorocarbonyl isocyanate in excellent yields. Subsequent alkylation with N-protected amino alcohols afforded the desired 1,3,5-triazine-2,4,6-triones in good yields. This methodology was applied to the synthesis of a chemical library acting as antagonists of the hGnRH receptor. 相似文献
49.
Pontillo J Guo Z Wu D Struthers RS Chen C 《Bioorganic & medicinal chemistry letters》2005,15(19):4363-4366
Several efficient synthetic routes for 2-, 4-, and 6-aryl-1,2,4-triazine-3,5-diones were developed. Derivatives were synthesized and studied as gonadotropin-releasing hormone antagonists in an effort to understand structure-activity relationships of the monocyclic compounds. 相似文献
50.
Perry SJ Junger S Kohout TA Hoare SR Struthers RS Grigoriadis DE Maki RA 《The Journal of biological chemistry》2005,280(12):11560-11568
The corticotropin releasing factor (CRF) type 1 receptor (CRF1) is a class B family G protein-coupled receptor that regulates the hypothalamic-pituitary-adrenal stress axis. Astressin is an amino-terminal truncated analog of CRF that retains high affinity binding to the extracellular domain of the receptor and is believed to act as a neutral competitive antagonist of receptor activation. Here we show that despite being unable to activate the CRF1 receptor, astressin binding results in the internalization of the receptor. Furthermore, entirely different pathways of internalization of CRF1 receptors are utilized following CRF and astressin binding. CRF causes the receptor to be phosphorylated, recruit beta-arrestin2, and to be internalized rapidly, likely through clathrin-coated pits. Astressin, however, fails to induce receptor phosphorylation or beta-arrestin2 recruitment, and internalization is slow and occurs through a pathway that is insensitive to inhibitors of clathrin-coated pits and caveolae. The fate of the internalized receptors also differs because only CRF-induced internalization results in receptor down-regulation. Furthermore, we present evidence that for astressin to induce internalization it must interact with both the extracellular amino terminus and the juxtamembrane domain of the receptor. Astressin binds with 6-fold higher affinity to full-length CRF1 receptors than to a chimeric protein containing only the extracellular domain attached to the transmembrane domain of the activin IIB receptor, yet two 12-residue analogs of astressin have similar affinities for both proteins but are unable to induce receptor internalization. These data demonstrate that agonists and antagonists for CRF1 receptors promote distinct conformations, which are then differentially regulated. 相似文献