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1.
McCombie SW Lin SI Tagat JR Nazareno D Vice S Ford J Asberom T Leone D Kozlowski JA Zhou G Ruperto VB Duffy RA Lachowicz JE 《Bioorganic & medicinal chemistry letters》2002,12(5):795-798
The synthesis and muscarinic binding properties of compounds based on the 1-[4-(4-arylsulfonyl)phenylmethyl]-4-(1-aroyl-4-piperidinyl)-piperazine skeleton are described. For compounds, substituted with appropriately configured methyl groups at the benzylic center and at the piperazine 2-position, high levels of selective, M(2) subtype affinity could be obtained, particularly when the terminal N-aroyl residue was ortho-substituted. 相似文献
2.
T.K. Sasikumar Duane A. Burnett Theodros Asberom Wen-Lian Wu Chad Bennett David Cole Ruo Xu William J. Greenlee John Clader Lili Zhang Lynn Hyde 《Bioorganic & medicinal chemistry letters》2010,20(12):3645-3648
Complex tetracyclic sulfones were designed as γ-secretase inhibitors and a stereoselective synthesis was achieved. γ-Secretase activity was seen predominately in the (?) enantiomeric series. Compounds such as 2a and 2b showed remarkable in vitro and in vivo potency. 相似文献
3.
Josien H Bara T Rajagopalan M Asberom T Clader JW Favreau L Greenlee WJ Hyde LA Nomeir AA Parker EM Pissarnitski DA Song L Wong GT Zhang L Zhang Q Zhao Z 《Bioorganic & medicinal chemistry letters》2007,17(19):5330-5335
The design and development of a new class of small 2,6-disubstituted piperidine N-arylsulfonamide gamma-secretase inhibitors is reported. Lowering molecular weight including the use of conformational constraint led to compounds with less CYP 3A4 liability compared to early leads. Compounds active orally in lowering Abeta levels in Tg CRND8 mice were identified as potential treatments for Alzheimer's disease. 相似文献
4.
Identification of presenilin 1-selective γ-secretase inhibitors with reconstituted γ-secretase complexes 总被引:1,自引:0,他引:1
Lee J Song L Terracina G Bara T Josien H Asberom T Sasikumar TK Burnett DA Clader J Parker EM Zhang L 《Biochemistry》2011,50(22):4973-4980
Accumulation of the β-amyloid (Aβ) peptides is one of the major pathologic hallmarks in the brains of Alzheimer's disease (AD) patients. Aβ is generated by sequential proteolytic cleavage of the amyloid precursor protein (APP) catalyzed by β- and γ-secretases. Inhibition of Aβ production by γ-secretase inhibitors (GSIs) is thus being pursued as a target for treatment of AD. In addition to processing APP, γ-secretase also catalyzes proteolytic cleavage of other transmembrane substrates, with the best characterized one being the cell surface receptor Notch. GSIs reduce Aβ production in animals and humans but also cause significant side effects because of the inhibition of Notch processing. The development of GSIs that reduce Aβ production and have less Notch-mediated side effect liability is therefore an important goal. γ-Secretase is a large membrane protein complex with four components, two of which have multiple isoforms: presenilin (PS1 or PS2), aph-1 (aph-1a or aph-1b), nicastrin, and pen-2. Here we describe the reconstitution of four γ-secretase complexes in Sf9 cells containing PS1--aph-1a, PS1--aph-1b, PS2--aph-1a, and PS2--aph-1b complexes. While PS1--aph-1a, PS1--aph-1b, and PS2--aph-1a complexes displayed robust γ-secretase activity, the reconstituted PS2--aph-1b complex was devoid of detectable γ-secretase activity. γ-Secretase complexes containing PS1 produced a higher proportion of the toxic species Aβ42 than γ-secretase complexes containing PS2. Using the reconstitution system, we identified MRK-560 and SCH 1500022 as highly selective inhibitors of PS1 γ-secretase activity. These findings may provide important insights into developing a new generation of γ-secretase inhibitors with improved side effect profiles. 相似文献
5.
Theodros Bedelu Amare Gessesse Dawit Abate 《World journal of microbiology & biotechnology》1998,14(5):731-734
A comparison of the nematode-destroying capability of two nematophagous Arthrobotrys spp. (coded ART-1 and ART-2), isolated from soil samples, showed that ART-1 (LD50=290conidia/ml) was more efficient than ART-2 (LD50=725conidia/ml). The two isolates produce extracellular proteases in liquid culture. The proteases from both isolates had a temperature optimum of 50°C. The optimum pH for protease activity was in the range of 7.5–8 for ART-1 and 7.5–9 for ART-2. ART-1 produced more protease activity (13.3±0.72U/ml) than ART-2 (10.9±0.375U/ml). The proteases from ART-1 were more efficient in degrading nematodes than those of ART-2 by virtue of being produced in a larger quantity. We suggest that the difference in the nematode-destroying capability between the two strains is solely the result of the difference in the amount of extracellular proteases they produce. 相似文献
6.
Boyle CD Xu R Asberom T Chackalamannil S Clader JW Greenlee WJ Guzik H Hu Y Hu Z Lankin CM Pissarnitski DA Stamford AW Wang Y Skell J Kurowski S Vemulapalli S Palamanda J Chintala M Wu P Myers J Wang P 《Bioorganic & medicinal chemistry letters》2005,15(9):2365-2369
In search of a PDE5 inhibitor for erectile dysfunction, an SAR was developed from a PDE1/PDE5 purine series of leads, which had modest PDE5 potency and poor isozyme selectivity. A compound (41) with PDE5 inhibition and in vivo activity similar to sildenafil was discovered from this effort. In addition, purine 41 demonstrated superior overall PDE isozyme selectivity when compared to the approved PDE5 inhibitors sildenafil, vardenafil, and tadalafil, which may result in a more favorable side-effect profile. 相似文献
7.
Liu N Lo LS Askary SH Jones L Kidane TZ Trang T Nguyen M Goforth J Chu YH Vivas E Tsai M Westbrook T Linder MC 《The Journal of nutritional biochemistry》2007,18(9):597-608
Transcuprein is a high-affinity copper carrier in the plasma that is involved in the initial distribution of copper entering the blood from the digestive tract. To identify and obtain cDNA for this protein, it was purified from rat plasma by size exclusion and copper-chelate affinity chromatography, and amino acid sequences were obtained. These revealed a 190-kDa glycosylated protein identified as the macroglobulin alpha(1)-inhibitor III, the main macroglobulin of rodent blood plasma. Albumin (65 kDa) copurified in variable amounts and was concluded to be a contaminant (although it can transiently bind the macroglobulin). The main macroglobulin in human blood plasma (alpha(2)-macroglobulin), which is homologous to alpha(1)-inhibitor III, also bound copper tightly. Expression of alpha(1)I3 (transcuprein) mRNA by the liver was examined in rats with and without copper deficiency, using quantitative polymerase chain reaction methodology and Northern blot analysis. Protein expression was examined by Western blotting. Deficient rats with 40% less ceruloplasmin oxidase activity and liver copper concentrations expressed about twice as much alpha(1)I3 mRNA, but circulating levels of transcuprein did not differ. Iron deficiency, which increased liver copper concentrations by threefold, reduced transcuprein mRNA expression and circulating levels of transcuprein relative to what occurred in rats with normal or excess iron. We conclude that transcupreins are specific macroglobulins that not only carry zinc but also carry transport copper in the blood, and that their expression can be modulated by copper and iron availability. 相似文献
8.
Wang Y Chackalamannil S Hu Z Boyle CD Lankin CM Xia Y Xu R Asberom T Pissarnitski D Stamford AW Greenlee WJ Skell J Kurowski S Vemulapalli S Palamanda J Chintala M Wu P Myers J Wang P 《Bioorganic & medicinal chemistry letters》2002,12(21):3149-3152
We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC(50)=0.6 nM, PDE6/PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC(50)=3.5 nM, PDE6/PDE5=7). 相似文献
9.
Release of iron from ferritin requires lysosomal activity 总被引:4,自引:0,他引:4
How ferritin-Fe becomes available for cell functions is unknown. Our previous studies with rat hepatoma cells indicated ferritin had to be degraded to release its Fe. In these studies, we investigated whether this occurs in other cell types and whether lysosomes are required. Release of ferritin-Fe was induced with desferoxamine (DFO) in 59Fe-preloaded hepatoma, Caco2, and erythroid K562 cells and measured by rocket immunoelectrophoresis and autoradiography. The half-lives for ferritin-59Fe and protein were parallel (23, 16, and 11 h for the hepatic, Caco2, and K562 cells, respectively). Co-treatment with 180 µM Fe, leupeptin, chymostatin, or chloroquine markedly decreased rates of ferritin-Fe release and ferritin degradation. Lactacystin had no effect except for a small one in erythroid cells. Fractionation of hepatoma cell lysates on iodixanol gradients showed rapid depletion of cytosolic ferritin by DFO treatment but no accumulation in lysosomes. We conclude that regardless of cell type, release of Fe from ferritin occurs mainly through lysosomal proteolysis. degradation; proteasomes 相似文献
10.
Ruo Xu David Cole Ted Asberom Tom Bara Chad Bennett Duane A. Burnett John Clader Martin Domalski William Greenlee Lynn Hyde Hubert Josien Hongmei Li Mark McBriar Brian McKittrick Andrew T. McPhail Dmitri Pissarnitski Li Qiang Murali Rajagopalan Thavalakulamgar Sasikumar Jing Su Zhiqiang Zhao 《Bioorganic & medicinal chemistry letters》2010,20(8):2591-2596
A novel series of tricyclic γ-secretase inhibitors was designed and synthesized via a conformational analysis of literature compounds. The preliminary results have shown that compounds in this new series have much improved in vitro potency and in vivo profiles. More importantly, they have greatly reduced Notch related toxicity that was associated with previous γ-secretase inhibitors. 相似文献