排序方式: 共有51条查询结果,搜索用时 31 毫秒
1.
Grover GJ Atwal KS Sleph PG Wang FL Monshizadegan H Monticello T Green DW 《American journal of physiology. Heart and circulatory physiology》2004,287(4):H1747-H1755
Mitochondrial F(1)F(0)-ATPase normally synthesizes ATP in the heart, but under ischemic conditions this enzyme paradoxically causes ATP hydrolysis. Nonselective inhibitors of this enzyme (aurovertin, oligomycin) inhibit ATP synthesis in normal tissue but also inhibit ATP hydrolysis in ischemic myocardium. We characterized the profile of aurovertin and oligomycin in ischemic and nonischemic rat myocardium and compared this with the profile of BMS-199264, which only inhibits F(1)F(0)-ATP hydrolase activity. In isolated rat hearts, aurovertin (1-10 microM) and oligomycin (10 microM), at concentrations inhibiting ATPase activity, reduced ATP concentration and contractile function in the nonischemic heart but significantly reduced the rate of ATP depletion during ischemia. They also inhibited recovery of reperfusion ATP and contractile function, consistent with nonselective F(1)F(0)-ATPase inhibitory activity, which suggests that upon reperfusion, the hydrolase activity switches back to ATP synthesis. BMS-199264 inhibits F(1)F(0) hydrolase activity in submitochondrial particles with no effect on ATP synthase activity. BMS-199264 (1-10 microM) conserved ATP in rat hearts during ischemia while having no effect on preischemic contractile function or ATP concentration. Reperfusion ATP levels were replenished faster and necrosis was reduced by BMS-199264. ATP hydrolase activity ex vivo was selectively inhibited by BMS-199264. Therefore, excessive ATP hydrolysis by F(1)F(0)-ATPase contributes to the decline in cardiac energy reserve during ischemia and selective inhibition of ATP hydrolase activity can protect ischemic myocardium. 相似文献
2.
Hamann LG Ding CZ Miller AV Madsen CS Wang P Stein PD Pudzianowski AT Green DW Monshizadegan H Atwal KS 《Bioorganic & medicinal chemistry letters》2004,14(4):1031-1034
A series of benzodiazepine-based inhibitors of mitochondrial F(1)F(0) ATP hydrolase were prepared and evaluated for their ability to selectively inhibit the enzyme in the forward direction. Compounds from this series showed excellent potency and selectivity for ATP hydrolase versus ATP synthase, suggesting a potentially beneficial profile useful for the treatment of ischemic heart disease. 相似文献
3.
Ahmad S Ngu K Combs DW Wu SC Weinstein DS Liu W Chen BC Chandrasena G Dorso CR Kirby M Atwal KS 《Bioorganic & medicinal chemistry letters》2004,14(1):177-180
Inhibition of the sodium hydrogen exchanger isoform-1 (NHE-1) has been shown to limit damage to the myocardium under ischemic conditions in animals. While most known NHE-1 inhibitors are acylguanidines, this report describes the design and synthesis of a series of heterocyclic inhibitors of NHE-1 including aminoimidazoles with undiminished in vitro activity and oral bioavailability. 相似文献
4.
Atwal KS Ahmad S Ding CZ Stein PD Lloyd J Hamann LG Green DW Ferrara FN Wang P Rogers WL Doweyko LM Miller AV Bisaha SN Schmidt JB Li L Yost KJ Lan HJ Madsen CS 《Bioorganic & medicinal chemistry letters》2004,14(4):1027-1030
A series of substituted guanidine derivatives were prepared and evaluated as potent and selective inhibitors of mitochondrial F(1)F(0) ATP hydrolase. The initial thiourethane derived lead molecules possessed intriguing in vitro pharmacological profiles, though contained moieties considered non-drug-like. Analogue synthesis efforts led to compounds with maintained potency and superior physical properties. Small molecules in this series which potently and selectivity inhibit ATP hydrolase and not ATP synthase may have utility as cardioprotective agents. 相似文献
5.
Shi Y O'Connor SP Sitkoff D Zhang J Shi M Bisaha SN Wang Y Li C Ruan Z Lawrence RM Klei HE Kish K Liu EC Seiler SM Schweizer L Steinbacher TE Schumacher WA Robl JA Macor JE Atwal KS Stein PD 《Bioorganic & medicinal chemistry letters》2011,21(24):7516-7521
The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide–valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC50 of 7 nM and EC2×PT of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide–valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets. 相似文献
6.
7.
Atwal GS Rabadán R Lozano G Strong LC Ruijs MW Schmidt MK van't Veer LJ Nevanlinna H Tommiska J Aittomäki K Bougeard G Frebourg T Levine AJ Bond GL 《PloS one》2008,3(4):e1951
Germline genetics, gender and hormonal-signaling pathways are all well described modifiers of cancer risk and progression. Although an improved understanding of how germline genetic variants interact with other cancer risk factors may allow better prevention and treatment of human cancer, measuring and quantifying these interactions is challenging. In other areas of research, Information Theory has been used to quantitatively describe similar multivariate interactions. We implemented a novel information-theoretic analysis to measure the joint effect of a high frequency germline genetic variant of the p53 tumor suppressor pathway (MDM2 SNP309 T/G) and gender on clinical cancer phenotypes. This analysis quantitatively describes synergistic interactions among gender, the MDM2 SNP309 locus, and the age of onset of tumorigenesis in p53 mutation carriers. These results offer a molecular and genetic basis for the observed sexual dimorphism of cancer risk in p53 mutation carriers and a model is proposed that suggests a novel cancer prevention strategy for p53 mutation carriers. 相似文献
8.
Finlay HJ Lloyd J Nyman M Conder ML West T Levesque P Atwal K 《Bioorganic & medicinal chemistry letters》2008,18(8):2714-2718
The design and synthesis of a series of highly functionalized pyrano-[2,3b]-pyridines is described. These compounds were assayed for their ability to block the I(Kur) channel encoded by the gene hKV1.5 in patch-clamped L-929 cells. Six of the compounds in this series showed sub-micromolar activity, the most potent being 4-(4-ethyl-benzenesulfonylamino)-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-pyrano[2,3b]-pyridine-6-carboxylic acid ethyl-phenyl-amide with an IC(50) of 378 nM. 相似文献
9.
When growth regulatory genes are damaged in a cell, it may become cancerous.
Current technological advances in the last decade have allowed the
characterization of the whole genome of these cells by directly or indirectly
measuring DNA changes. Complementary analyses were developed to make sense of
the massive amounts of data generated. A large majority of these analyses were
developed to construct interaction networks between genes from, primarily,
expression array data. We review the current technologies and analyses that have
developed in the last decade. We further argue that as cancer genomics evolves
from single gene validations to gene network inferences, new analyses must be
developed for the different technological platforms. 相似文献
10.
Richard Copin Alina Baum Elzbieta Wloga Kristen E. Pascal Stephanie Giordano Benjamin O. Fulton Anbo Zhou Nicole Negron Kathryn Lanza Newton Chan Angel Coppola Joyce Chiu Min Ni Yi Wei Gurinder S. Atwal Annabel Romero Hernandez Kei Saotome Yi Zhou Christos A. Kyratsous 《Cell》2021,184(15):3949-3961.e11
- Download : Download high-res image (122KB)
- Download : Download full-size image