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941.
Tan Q Birzin ET Chan W Yang YT Pai LY Hayes EC DaSilva CA DiNinno F Rohrer SP Schaeffer JM Hammond ML 《Bioorganic & medicinal chemistry letters》2004,14(14):3753-3755
Dihydrobenzodithiin compounds (1-6) were prepared to explore the expansion of the dihydrobenzoxathiin lead compounds I-III as SERAMs (Selective Estrogen Receptor Alpha Modulators). The dihydrobenzodithiin compounds generally maintained a high degree of selectivity for ERalpha over ERbeta, however, they lacked the in vivo antagonism/agonism activity exhibited by the lead class in an immature rat uterine growth model. 相似文献
942.
Parmee ER He J Mastracchio A Edmondson SD Colwell L Eiermann G Feeney WP Habulihaz B He H Kilburn R Leiting B Lyons K Marsilio F Patel RA Petrov A Di Salvo J Wu JK Thornberry NA Weber AE 《Bioorganic & medicinal chemistry letters》2004,14(1):43-46
Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice. 相似文献
943.
Lovering F Angell Y Zhang YL Bridges K 《Bioorganic & medicinal chemistry letters》2004,14(20):5081-5083
In an effort to identify new approaches to lead discovery a polyvalent assay was developed to allow identification of weak inhibitors. This approach involves the polyvalent display of a protein binder off a Tenta-gel scaffold and the generation of a polyvalent display of protein by biotinylation followed by complexation with fluorescently labeled streptavidin. Subsequent exposure of the streptavidin complexed protein to Tenta-gel beads with active protein binders results in fluorescent beads, which are easily viewed under a fluorescent microscope. 相似文献
944.
Lu T Markotan T Coppo F Tomczuk B Crysler C Eisennagel S Spurlino J Gremminger L Soll RM Giardino EC Bone R 《Bioorganic & medicinal chemistry letters》2004,14(14):3727-3731
Through structure-based drug design and parallel synthesis, we have discovered a novel series of nonpeptidic phenyl-based thrombin inhibitors using oxyguanidines as guanidine bioisosteres. These compounds have been found to be highly potent, highly selective, and orally bioavailable. 相似文献
945.
Niu C Smith D Zask A Loganzo F Discafani C Beyer C Greenberger L Ayral-Kaloustian S 《Bioorganic & medicinal chemistry letters》2004,14(16):4329-4332
Modifications of the B-segment of HTI-286 (2) produced a class of analogs incorporating heteroatom-substituents. The structure-activity relationship was studied. Analogs bearing methylsulfide and fluoride groups exhibited potency comparable to that of the parent compound HTI-286 and to paclitaxel in cytotoxicity assays against KB-3-1 cell lines. These analogs were more potent than paclitaxel against P-glycoprotein expressing KB-8-5 and KB-V1 cell lines. Several analogs showed strong inhibition of tubulin polymerization. 相似文献
946.
Helal CJ Sanner MA Cooper CB Gant T Adam M Lucas JC Kang Z Kupchinsky S Ahlijanian MK Tate B Menniti FS Kelly K Peterson M 《Bioorganic & medicinal chemistry letters》2004,14(22):5521-5525
High-throughput screening with cyclin-dependent kinase 5 (cdk5)/p25 led to the discovery of N-(5-isopropyl-thiazol-2-yl)isobutyramide (1). This compound is an equipotent inhibitor of cdk5 and cyclin-dependent kinase 2 (cdk2)/cyclin E (IC(50)=ca. 320nM). Parallel and directed synthesis techniques were utilized to explore the SAR of this series. Up to 60-fold improvements in potency at cdk5 and 12-fold selectivity over cdk2 were achieved. 相似文献
947.
Peat AJ Boucheron JA Dickerson SH Garrido D Mills W Peckham J Preugschat F Smalley T Schweiker SL Wilson JR Wang TY Zhou HQ Thomson SA 《Bioorganic & medicinal chemistry letters》2004,14(9):2121-2125
A series of [1-aryl-1H-pyrazolo[3,4-d]pyrimidin-4-yl]arylhydrazones were discovered as novel inhibitors glycogen synthase kinase-3 (GSK-3). Based on initial modeling a detailed SAR was constructed. Modification of the interior binding aryl ring (Ar(1)) determined this to be a tight binding region with little room for modification. As predicted from the model, a large variety of modifications could be incorporated into the hydrazone aryl ring. This work led to GSK-3 inhibitors in the low nano-molar range. 相似文献
948.
Sengpiel F 《Current biology : CB》2004,14(23):R997-R999
It is commonly thought that neural activity in the visual cortex reflects retinal input. Recent studies, however, suggest that patterns of cortical activity are mostly intrinsically generated, and that visual input exerts but a modulatory influence. 相似文献
949.
Genome sequence of the lignocellulose degrading fungus Phanerochaete chrysosporium strain RP78 总被引:7,自引:0,他引:7
Martinez D Larrondo LF Putnam N Gelpke MD Huang K Chapman J Helfenbein KG Ramaiya P Detter JC Larimer F Coutinho PM Henrissat B Berka R Cullen D Rokhsar D 《Nature biotechnology》2004,22(6):695-700
White rot fungi efficiently degrade lignin, a complex aromatic polymer in wood that is among the most abundant natural materials on earth. These fungi use extracellular oxidative enzymes that are also able to transform related aromatic compounds found in explosive contaminants, pesticides and toxic waste. We have sequenced the 30-million base-pair genome of Phanerochaete chrysosporium strain RP78 using a whole genome shotgun approach. The P. chrysosporium genome reveals an impressive array of genes encoding secreted oxidases, peroxidases and hydrolytic enzymes that cooperate in wood decay. Analysis of the genome data will enhance our understanding of lignocellulose degradation, a pivotal process in the global carbon cycle, and provide a framework for further development of bioprocesses for biomass utilization, organopollutant degradation and fiber bleaching. This genome provides a high quality draft sequence of a basidiomycete, a major fungal phylum that includes important plant and animal pathogens. 相似文献
950.
Rogers KD Seebacher F Thompson MB 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2004,137(4):1023-738
We measured the rate at which the metabolic enzymes lactate dehydrogenase (LDH), citrate synthase (CS), and cytochrome c oxidase (CCO) acclimate in the response to lowered temperature in the axial muscle of tadpoles of Limnodynastes peronii (Anura: Myobatrachidae) over 6 weeks. In addition, we measured growth rates of the tadpoles kept at both temperatures and examined the activities of these enzymes in the liver tissue of the control group and cold-acclimated group at the end of the experiment. We found that LDH acclimates in axial muscle; the differences between the control and cold-acclimated group became apparent after 21 days. After 42 days, the activity of LDH in axial muscle in the cold-acclimated group was 30% greater than the control group. Growth rates were maintained at 0.7 mm/week within both treatments despite the 10 degrees C difference in temperature between experimental groups. Both LDH and CS were increased in activity in the liver (5 and 1.3 times greater, respectively, in the cold-acclimated group). The thermal sensitivity (Q(10)) of LDH was between 20 and 30 degrees C in the cold-acclimated group (1.2+/-0.01) when compared to the control group (1.6+/-0.15). The rate at which acclimation in this species occurs is appropriate for seasonal changes in temperature, and these animals may not be able to respond to a rapid drop in temperature. 相似文献