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991.
Edwards PD Albert JS Sylvester M Aharony D Andisik D Callaghan O Campbell JB Carr RA Chessari G Congreve M Frederickson M Folmer RH Geschwindner S Koether G Kolmodin K Krumrine J Mauger RC Murray CW Olsson LL Patel S Spear N Tian G 《Journal of medicinal chemistry》2007,50(24):5912-5925
Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization. 相似文献
992.
Bunnage ME Blagg J Steele J Owen DR Allerton C McElroy AB Miller D Ringer T Butcher K Beaumont K Evans K Gray AJ Holland SJ Feeder N Moore RS Brown DG 《Journal of medicinal chemistry》2007,50(24):6095-6103
Thrombin-activatable fibrinolysis inhibitor (TAFI) has emerged as a key link between the coagulation and fibrinolysis cascades and represents a promising new target for the treatment of thrombosis. A novel series of imidazolepropionic acids has been designed that exhibit high potency against activated TAFI (TAFIa) and excellent selectivity over plasma carboxypeptidase N (CPN). Structure activity relationships suggest that the imidazole moiety plays a key role in binding to the catalytic zinc of TAFIa, and this has been supported by crystallographic studies using porcine pancreatic carboxypeptidase B as a surrogate for TAFIa. The SAR program led to the identification of 21 (TAFIa Ki = 10 nM, selectivity TAFIa/CPN > 1000) as a candidate for clinical development. Compound 21 exhibited antithrombotic efficacy in a rabbit model of venous thrombosis, yet had no effect on surgical bleeding in the rabbit. In addition, 21 exhibited an excellent preclinical and clinical pharmacokinetic profile, characterized by paracellular absorption, low clearance, and a low volume of distribution, fully consistent with its physicochemical properties of low molecular weight (MW = 239) and high hydrophilicity (log D = -2.8). These data indicate 21 (UK-396,082) has potential as a novel TAFIa inhibitor for the treatment of thrombosis and other fibrin-dependent diseases in humans. 相似文献
993.
Murray CW Callaghan O Chessari G Cleasby A Congreve M Frederickson M Hartshorn MJ McMenamin R Patel S Wallis N 《Journal of medicinal chemistry》2007,50(6):1116-1123
This paper describes an application of fragment screening to the aspartyl protease enzyme, beta-secretase (BACE-1), using high throughput X-ray crystallography. Three distinct chemotypes were identified by X-ray crystallography as binding to the catalytic aspartates either via an aminoheterocycle (such as 2-aminoquinoline), a piperidine, or an aliphatic hydroxyl group. The fragment hits were weak inhibitors of BACE-1 in the millimolar range but were of interest because most of them displayed relatively good ligand efficiencies. The aminoheterocycles exhibited a novel recognition motif that has not been seen before with aspartic proteases. Virtual screening around this motif identified an aminopyridine with increased potency and attractive growth points for further elaboration using structure-based drug design. The companion paper illustrates how sub-micromolar inhibitors were developed starting from this fragment. 相似文献
994.
Scott AT Hendry TM Iaquinto JM Owen JR Wayne JS Adelaar RS 《Foot & ankle international / American Orthopaedic Foot and Ankle Society [and] Swiss Foot and Ankle Society》2007,28(11):1143-1153
BACKGROUND: Bony procedures play an essential role in the operative treatment of stage II posterior tibial tendon insufficiency and often substantially alter the loading characteristics of the foot. METHODS: Eight matched pairs of cadaver lower extremities were axially loaded onto a TekScan HR Mat. (TekScan, Inc., South Boston, MA) After intact testing, each specimen had a lateral column lengthening (either a calcaneocuboid distraction arthrodesis [CCDA] or Evans procedure), a medializing calcaneal osteotomy (MCO), and a plantarflexion (Cotton) osteotomy of the medial cuneiform. The measured plantar pressures were divided into three forefoot regions, two midfoot regions, and two hindfoot regions. For each region, average pressure, peak pressure, and contact area data were collected. RESULTS: Despite the fact that both lateral column lengthening procedures resulted in increased lateral forefoot pressures, no significant differences were noted between the CCDA and the Evans procedure. The addition of a MCO did not significantly alter the plantar pressures measured after the lateral column lengthening alone. Although the Cotton osteotomy resulted in increased average pressures within the medial forefoot, a compensatory significant decrease in lateral forefoot pressures was not observed. CONCLUSIONS: The present study demonstrated increased lateral forefoot pressures after a combined lateral column lengthening and MCO and does not support the idea that a Cotton osteotomy significantly reduces loading of the lateral forefoot. CLINICAL RELEVANCE: The incidence of lateral forefoot pain and fifth metatarsal stress fractures subsequent to either lateral column lengthening procedure may not significantly decline after a Cotton osteotomy. 相似文献
995.
Chapuis PH Chan C Lin BP Armstrong K Armstrong B Spigelman AD O'Connell D Leong D Dent OF 《ANZ journal of surgery》2007,77(11):963-969
BACKGROUND: The aim of this study was to determine the extent to which pathology reporting of colorectal cancers notified to the New South Wales Central Cancer Registry during 2000 conformed to guidelines promulgated by the National Health and Medical Research Council. METHODS: De-identified reports for 2233 resected specimens of primary invasive colorectal carcinoma were coded according to a standardized system to compile information on 28 clinical and pathology features. An overall score for each report was calculated by computing the number out of 13 essential features specified in the guidelines for which data had been recorded explicitly and unambiguously in the report. RESULTS: The overall score ranged from 3 to 13 features with a mean of 9. No more than 7 features were reported explicitly in just less than one quarter of the reports and no more than 10 in three quarters. There were only 110 reports (4.9%) that included all features. Information on direct spread and nodal metastasis was well reported; resection margins less so. Many reports lacked information on metastases beyond the operative field, the involvement of deep or circumferential resection margins and tumour stage. CONCLUSION: In some respects pathology reports of resected colorectal cancer specimens displayed a high level of completeness. Some important features, however, were poorly described. Reporting could be improved if surgeons were to use a standardized form to convey clinical information to the pathologist and if pathologists were to report in a structured or synoptic format, explicitly recording the presence or absence of each feature in a standard list. 相似文献
996.
997.
Ralph D Eardley I Kell P Dean J Hackett G Collins O Edwards D 《BJU international》2007,100(1):130-136
OBJECTIVE: To evaluate the effect of vardenafil on both erectile function (EF) and treatment satisfaction (an aspect of quality of life) in men and their partners, as erectile dysfunction (ED) has a profound effect on patients' quality of life and that of their partners, and treatment for ED tends to be focused on improving functional measures of EF. PATIENTS, SUBJECTS AND METHODS: For this randomized, double-blind, placebo-controlled trial, men with ED for >6 months, according to the USA National Institutes of Health Consensus Statement, were recruited. In all, 611 patients were randomized to treatment with either vardenafil (10 mg for 4 weeks, titrated to preferred dose, 5, 10 or 20 mg, during the next 8 weeks, and maintained at preferred dose for the following 14 weeks), or placebo. RESULTS: At 18 weeks (primary endpoint), the mean improvement in the EF domain of International Index of EF (IIEF-EF) vs baseline was significantly greater with vardenafil than placebo (12.70 vs 1.69, P < 0.001). This was accompanied by significant benefits at 26 weeks and in various secondary variables relating to sexual satisfaction. Qualitative assessment of the treatment effect revealed three categories of importance to patients: effectiveness, confidence and quality of life. There were significant linear correlations between patients' EF and treatment satisfaction, and between patients' EF and their partners' treatment satisfaction. CONCLUSIONS: Functional improvements in response to vardenafil treatment are significantly correlated with treatment satisfaction for both patients with ED and their partners. These findings apply to patients with a wide range of baseline characteristics. 相似文献
998.
999.
Managing asthma around peers can be stressful for young adolescents (age 9–14). However, the contexualised coping activities under asthma management-related peer stress is under-investigated. The study aims to explore the peer stress-related coping strategies young adolescents adopt in asthma management. Thirty-four young adolescents were interviewed with semi-structured storytelling protocols. Young adolescents expressed their opinions about four scenarios where the characters had difficulties managing asthma among peers. Interviews were transcribed, and qualitative data were analysed with analytical induction and constant comparison to generate themes that described the coping activities young adolescents adopted in four asthma management scenarios. Young adolescents' responses in each scenario were summarised. The coping activities adolescents adopted were cognitive justifying, explaining, outsourcing and undisclosing. Despite the limitations in a scenario-based qualitative study, the results may be useful for teachers and health professionals in social skill interventions for asthma management in early adolescence. 相似文献
1000.
Owen Dyer 《British medical journal》2001,322(7280):192