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131.
David C. Pryde Martin Corless David R. Fenwick Helen J. Mason Blanda C. Stammen Peter T. Stephenson David Ellis David Bachelor David Gordon Christopher G. Barber Anthony Wood Donald S. Middleton David C. Blakemore Gemma C. Parsons Rachel Eastwood Michelle Y. Platts Keith Statham Kerry A. Paradowski Catherine Burt Wolfgang Klute 《Bioorganic & medicinal chemistry letters》2009,19(4):1084-1088
The synthesis of a range of novel amine-containing structures and their primary potency as inhibitors of HIV-1 fusion via blocking of the CCR5 receptor is described. The development of the medicinal chemistry strategy and SAR’s which led to the identification of the piperidine amide compounds 33 and 36 as excellent leads for further evaluation is described, along with key physicochemical data which highlighted their lead potential. 相似文献
132.
Diego A. Oyarzún Brian P. Ingalls Richard H. Middleton Dimitrios Kalamatianos 《Bulletin of mathematical biology》2009,71(8):1851-1872
The regulation of cellular metabolism facilitates robust cellular operation in the face of changing external conditions. The
cellular response to this varying environment may include the activation or inactivation of appropriate metabolic pathways.
Experimental and numerical observations of sequential timing in pathway activation have been reported in the literature. It
has been argued that such patterns can be rationalized by means of an underlying optimal metabolic design. In this paper we
pose a dynamic optimization problem that accounts for time-resource minimization in pathway activation under constrained total
enzyme abundance. The optimized variables are time-dependent enzyme concentrations that drive the pathway to a steady state
characterized by a prescribed metabolic flux. The problem formulation addresses unbranched pathways with irreversible kinetics.
Neither specific reaction kinetics nor fixed pathway length are assumed.
In the optimal solution, each enzyme follows a switching profile between zero and maximum concentration, following a temporal
sequence that matches the pathway topology. This result provides an analytic justification of the sequential activation previously
described in the literature. In contrast with the existent numerical approaches, the activation sequence is proven to be optimal
for a generic class of monomolecular kinetics. This class includes, but is not limited to, Mass Action, Michaelis–Menten,
Hill, and some Power-law models. This suggests that sequential enzyme expression may be a common feature of metabolic regulation,
as it is a robust property of optimal pathway activation. 相似文献
133.
Middleton DS Andrews M Glossop P Gymer G Jessiman A Johnson PS Mackenny M Pitcher MJ Rooker T Stobie A Tang K Morgan P 《Bioorganic & medicinal chemistry letters》2006,16(5):1434-1439
A series of sertraline analogues 4-39 which possess polar groups on the fused tetrahydronaphthalene ring, targeting reduced V(d) as a strategy to reduce T(max) and increase rate of elevation of central 5-HT levels, were prepared. These studies led to the successful identification of 22a, which demonstrated equivalent pharmacology and metabolic stability to 1, but which possessed greatly reduced V(d) leading to significantly shorter T(max), in rat pharmacokinetic studies. 相似文献
134.
Huang S Li R Connolly PJ Emanuel S Middleton SA 《Bioorganic & medicinal chemistry letters》2006,16(18):4818-4821
A novel series of 2-amino-4-(7-azaindol-3-yl)pyrimidines was discovered as cyclin dependent kinase 1 (CDK1) inhibitors. The core structure was synthesized via Pd(II) catalyzed coupling reaction. A number of analogues showed good potency for CDK1 and exhibited cellular antiproliferation activity. The structure-activity relationship is described. 相似文献
135.
Bignan GC Battista K Connolly PJ Orsini MJ Liu J Middleton SA Reitz AB 《Bioorganic & medicinal chemistry letters》2006,16(13):3524-3528
A novel series of indoles and 1H-pyrrolo[2,3-b]pyridines having a piperidine ring at the 3-position were synthesized and found to bind with high affinity to the ORL-1 receptor. Structure-activity relationships at the piperidine nitrogen were investigated in each series. Substitution on the phenyl ring and nitrogen atom of the indole and 1H-pyrrolo[2,3-b]pyridine cores generated several selective high-affinity ligands that were agonists of the ORL-1 receptor. 相似文献
136.
Feline model of acute nipah virus infection and protection with a soluble glycoprotein-based subunit vaccine 总被引:1,自引:0,他引:1 下载免费PDF全文
Mungall BA Middleton D Crameri G Bingham J Halpin K Russell G Green D McEachern J Pritchard LI Eaton BT Wang LF Bossart KN Broder CC 《Journal of virology》2006,80(24):12293-12302
Nipah virus (NiV) and Hendra virus (HeV) are paramyxoviruses capable of causing considerable morbidity and mortality in a number of mammalian species, including humans. Case reports from outbreaks and previous challenge experiments have suggested that cats were highly susceptible to NiV infection, responding with a severe respiratory disease and systemic infection. Here we have assessed the cat as a model of experimental NiV infection and use it in the evaluation of a subunit vaccine comprised of soluble G glycoprotein (sG). Two groups of two adult cats each were inoculated subcutaneously with either 500 or 5,000 50% tissue culture infective dose(s) (TCID(50)) of NiV. Animals were monitored closely for disease onset, and extensive analysis was conducted on samples and tissues taken during infection and at necropsy to determine viral load and tissue tropism. All animals developed clinical disease 6 to 9 days postinfection, a finding consistent with previous observations. In a subsequent experiment, two cats were immunized with HeV sG and two were immunized with NiV sG. Homologous serum neutralizing titers were greater than 1:20,000, and heterologous titers were greater than 1:20,000 to 16-fold lower. Immunized animals and two additional naive controls were then challenged subcutaneously with 500 TCID(50) of NiV. Naive animals developed clinical disease 6 to 13 days postinfection, whereas none of the immunized animals showed any sign of disease. TaqMan PCR analysis of samples from naive animals revealed considerable levels of NiV genome in a wide range of tissues, whereas the genome was evident in only two immunized cats in only four samples and well below the limit of accurate detection. These results indicate that the cat provides a consistent model for acute NiV infection and associated pathogenesis and an effective subunit vaccine strategy appears achievable. 相似文献
137.
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139.
While disturbances such as fire, cutting, and grazing can be an important part of the conservation of natural lands, some adjustments to management designed to mimic natural disturbance may be necessary with ongoing and projected climate change. Stressed vegetation that is incapable of regeneration will be difficult to maintain if adults are experiencing mortality, and/or if their early life‐history stages depend on disturbance. A variety of active management strategies employing disturbance are suggested, including resisting, accommodating, or directing vegetation change by manipulating management intensity and frequency. Particularly if land‐use change is the main cause of vegetation stress, amelioration of these problems using management may help vegetation resist change (e.g. strategic timing of water release if a water control structure is available). Managers could direct succession by using management to push vegetation toward a new state. Despite the historical effects of management, some vegetation change will not be controllable as climates shift, and managers may have to accept some of these changes. Nevertheless, proactive measures may help managers achieve important conservation goals in the future. 相似文献
140.