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91.
Beswick P Charrier N Clarke B Demont E Dingwall C Dunsdon R Faller A Gleave R Hawkins J Hussain I Johnson CN MacPherson D Maile G Matico R Milner P Mosley J Naylor A O'Brien A Redshaw S Riddell D Rowland P Skidmore J Soleil V Smith KJ Stanway S Stemp G Stuart A Sweitzer S Theobald P Vesey D Walter DS Ward J Wayne G 《Bioorganic & medicinal chemistry letters》2008,18(3):1022-1026
This article is focusing on further optimization of previously described hydroxy ethylamine (HEA) BACE-1 inhibitors obtained from a focused library with the support of X-ray crystallography. Optimization of the non-prime side of our inhibitors and introduction of a 6-membered sultam substituent binding to Asn-294 as well as a fluorine in the C-2 position led to derivatives with nanomolar potency in cell-based assays. 相似文献
92.
Adrian Hall Susan H. Brown Christopher Budd Nicholas M. Clayton Gerard M.P. Giblin Paul Goldsmith Thomas G. Hayhow David N. Hurst Alan Naylor D. Anthony Rawlings Tiziana Scoccitti Alexander W. Wilson Wendy J. Winchester 《Bioorganic & medicinal chemistry letters》2009,19(2):497-501
Herein we describe the medicinal chemistry programme to identify a potential back-up compound to the EP1 receptor antagonist GW848687X. This work started with the lipophilic 1,2-biaryl benzene derivative 4 which displayed molecular weight of 414.9 g/mol and poor in vivo metabolic stability in the rat and resulted in the identification of compound 7i (GSK345931A) which demonstrated good metabolic stability in the rat and lower molecular weight (381.9 g/mol). In addition, 7i (GSK345931A) showed measurable CNS penetration in the mouse and rat and potent analgesic efficacy in acute and sub-chronic models of inflammatory pain. 相似文献
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Naylor LH Carter H FitzSimons MG Cable NT Thijssen DH Green DJ 《American journal of physiology. Heart and circulatory physiology》2011,300(2):H664-H669
This study aimed to determine the importance of repeated increases in blood flow to conduit artery adaptation, using an exercise-independent repeated episodic stimulus. Recent studies suggest that exercise training improves vasodilator function of conduit arteries via shear stress-mediated mechanisms. However, exercise is a complex stimulus that may induce shear-independent adaptations. Nine healthy men immersed their forearms in water at 42°C for three 30-min sessions/wk across 8 wk. During each session, a pneumatic pressure cuff was inflated around one forearm to unilaterally modulate heating-induced increases in shear. Forearm heating was associated with an increase in brachial artery blood flow (P<0.001) and shear rate (P<0.001) in the uncuffed forearm; this response was attenuated in the cuffed limb (P<0.005). Repeated episodic exposure to bilateral heating induced an increase in endothelium-dependent vasodilation in response to 5-min ischemic (P<0.05) and ischemic handgrip exercise (P<0.005) stimuli in the uncuffed forearm, whereas the 8-wk heating intervention did not influence dilation to either stimulus in the cuffed limb. Endothelium-independent glyceryl trinitrate responses were not altered in either limb. Repeated heating increases blood flow to levels that enhance endothelium-mediated vasodilator function in humans. These findings reinforce the importance of the direct impacts of shear stress on the vascular endothelium in humans. 相似文献
95.
The ability of Arizona Common and Coastal Bermuda grass [Cynodon dactylon (L.) Pers.] to synthesize amino acids and proteins during water stress was investigated. Amino acids were continually synthesized during the water stress treatments, but protein synthesis was inhibited and protein levels decreased. 相似文献
96.
Beta1 integrins regulate mammary gland proliferation and maintain the integrity of mammary alveoli 总被引:12,自引:0,他引:12
Li N Zhang Y Naylor MJ Schatzmann F Maurer F Wintermantel T Schuetz G Mueller U Streuli CH Hynes NE 《The EMBO journal》2005,24(11):1942-1953
Integrin-extracellular matrix interactions play important roles in the coordinated integration of external and internal cues that are essential for proper development. To study the role of beta1 integrin in the mammary gland, Itgbeta1(flox/flox) mice were crossed with WAPiCre transgenic mice, which led to specific ablation of beta1 integrin in luminal alveolar epithelial cells. In the beta1 integrin mutant mammary gland, individual alveoli were disorganized resulting from alterations in cell-basement membrane associations. Activity of focal adhesion kinase (FAK) was also decreased in mutant mammary glands. Luminal cell proliferation was strongly inhibited in beta1 integrin mutant glands, which correlated with a specific increase of p21 Cip1 expression. In a p21 Cip1 null background, there was a partial rescue of BrdU incorporation, providing in vivo evidence linking p21 Cip1 to the proliferative defect observed in beta1 integrin mutant glands. A connection between p21 Cip1 and beta1 integrin as well as FAK was also established in primary mammary cells. These results point to the essential role of beta1 integrin signaling in mammary epithelial cell proliferation. 相似文献
97.
Carbamoyl phosphate synthetase of pea shoots (Pisum sativum L.) was purified 101-fold. Its stability was greatly increased by the addition of substrates and activators. The enzyme was strongly inhibited by micromolar amounts of UMP (Ki less than 2 mum). UDP, UTP, TMP, and ADP were also inhibitory. AMP caused either slight activation (under certain conditions) or was inhibitory. Uridine nucleotides were competitive inhibitors, as was AMP, while ADP was a noncompetitive inhibitor. Enzyme activity was increased manyfold by the activator ornithine. Ornithine acted by increasing the affinity for Mg.ATP by a factor of 8 or more. Other activators were IMP, GMP, ITP, and GTP, IMP, like ornithine, increased the Michaelis constant for Mg.ATP. The activators ornithine, GMP, and IMP (but not GTP and ITP) completely reversed inhibition caused by pyrimidine nucleotides while increasing the inhibition caused by ADP and AMP. 相似文献
98.
This study compared the cardiac and ventilatory behaviour of disturbed and settled (48 h recovery) ovigerous Cancer pagurus with the behaviour of non‐ovigerous crabs. It also examined the effects of starvation and a sand substrate on ovigerous females. Ovigerous crabs had significantly lower heart rates than non‐ovigerous crabs. This implies that they have a reduced metabolic rate, confirmed by an earlier study which described lower rates of oxygen uptake in ovigerous crabs. Scaphognathite beat frequency was unaffected by either the presence of eggs, starvation or a sand substrate, but the amplitude of ventilatory pressure changes was higher in settled ovigerous females, implying greater force. The duration of periods of reversed ventilation was also substantially extended in ovigerous crabs, and disturbance caused a ten‐fold increase in the frequency of these reversals, resulting in ventilation being carried out in a predominantly reversed direction. It is suggested that these respiratory adaptations serve to ventilate the egg mass. Disturbance also led to a greater elevation of heart rate in ovigerous crabs, indicating that they are more prone to handling stress. Fed ovigerous crabs spent a higher percentage of time ventilating unilaterally; this response was lost following starvation. Starved ovigerous crabs had the lowest mean heart rate, highest mean ventilatory pressures and, when disturbed above a sand substrate, they showed the highest frequency of reversals of ventilation, possibly in association with their efforts to bury their abdomen bearing the egg mass. 相似文献
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100.