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51.
52.
Pruitt JR Batt DG Wacker DA Bostrom LL Booker SK McLaughlin E Houghton GC Varnes JG Christ DD Covington M Das AM Davies P Graden D Kariv I Orlovsky Y Stowell NC Vaddi KG Wadman EA Welch PK Yeleswaram S Solomon KA Newton RC Decicco CP Carter PH Ko SS 《Bioorganic & medicinal chemistry letters》2007,17(11):2992-2997
DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520. 相似文献
53.
Mahapatra A Mativandlela SP Binneman B Fourie PB Hamilton CJ Meyer JJ van der Kooy F Houghton P Lall N 《Bioorganic & medicinal chemistry》2007,15(24):7638-7646
The naphthoquinone 7-methyljuglone (5-hydroxy-7-methyl-1,4-naphthoquinone) has previously been isolated and identified as an active component of root extracts of Euclea natalensis which displays antitubercular activity. Herein, a series of synthetic and plant-derived naphthoquinone derivates of the 7-methyljuglone scaffold have been prepared and evaluated for antibacterial activity against Mycobacterium tuberculosis. Several of these compounds have been shown to operate as subversive substrates with mycothiol disulfide reductase. The absence of a direct correlation between antitubercular activity and subversive substrate efficiency with mycothiol disulfide reductase, might be a consequence of their non-specific reactivity with multiple biological targets (e.g. other disulfide reductases). 相似文献
54.
Intensive use of cytotoxic agents in multimodality therapeutic regimens has resulted in almost 80% five-year disease-free survival and cure in the majority of childhood cancer patients. However, such success has come at the expense of severe acute or delayed toxicities and an increased occurrence of secondary cancers. With an increasing understanding of the genetic changes that underlie transformation in childhood cancer, rational approaches using agents that target these transforming events are being developed. Current and future strategies in developing tumor-selective therapy using inhibitors of signaling pathways dysregulated in leukemias (FLT3, NOTCH1) and solid/brain tumors (ErbB1-4, IGF-IR, PTCH1), and the challenges in developing less toxic, but equally effective treatments in pediatric oncology are presented. 相似文献
55.
Leatherbarrow AJ Griffiths R Hart CA Kemp R Williams NJ Diggle PJ Wright EJ Sutherst J Houghton P French NP 《Environmental microbiology》2007,9(7):1772-1779
Campylobacter lari is a rare human pathogen most commonly associated with birds and shellfish. Little information has been published regarding its prevalence in other environments, or on its potential role as a reservoir of antibiotic resistance. In this study, we characterized 109 C. lari isolated from a range of hosts using pulsed-field gel electrophoresis of macro-restricted chromosomal DNA, and by determining their susceptibility to a panel of four antibiotics. Pulsed-field gel electrophoresis analysis showed C. lari to be genetically diverse, particularly in isolates from wild birds and environmental water. The most common composite macro-restriction profile (cMRP) was found in multiple hosts (cattle, badgers, wild birds and rabbits), and seven other cMRPs were recovered from more than one host. All isolates were resistant to nalidixic acid and ciprofloxacin. Resistance to erythromycin and ampicillin was uncommon, but was observed in isolates from wild birds, cattle, wild mammals and water samples. The presence of the same cMRP in multiple hosts provides further evidence of transmission between livestock, wildlife and the environment, or for a common source of infection. 相似文献
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The ectodysplasin pathway, comprising the ligand ectodysplasin, its receptor Edar and a dedicated death domain adaptor protein Edaradd, plays an important role in epidermal organ formation in mammals. Mutations in the genes encoding these proteins cause dysplasia or absence of teeth, sweat glands and hair follicles. However, the relative position of this pathway in the regulatory hierarchy directing follicle formation remains unclear. In this work, the chicken orthologs of Eda, Edar and Edaradd were cloned to exploit the temporal precision of the feather tract system in order to study the role of the ectodysplasin pathway. We find that these genes are expressed in a similar pattern during feather and hair development, with the notable difference that the ligand Eda, which is expressed in the epidermis of the mouse, is expressed in the dermis of the feather tract. Contrary to conclusions reached from the analysis of mutant mice, we find that localization of Edar expression to the nascent placode is coincident or subsequent to the local expression of other markers of placodal differentiation, and not an upstream event in tract patterning. Furthermore, forced expression of BMP and activated beta-catenin demonstrate that local expression of Edar is dictated by the interaction between these two pathways. These results suggest that activation of the ectodysplasin pathway may be permissive for activating signals to overcome signals that inhibit placode formation, but the function of this pathway in the specification of follicle initiation lies downstream of other patterning events. 相似文献
58.
Batt DG Houghton GC Roderick J Santella JB Wacker DA Welch PK Orlovsky YI Wadman EA Trzaskos JM Davies P Decicco CP Carter PH 《Bioorganic & medicinal chemistry letters》2005,15(3):787-791
The synthesis and structure-activity relationships of N-arylalkylpiperidylmethyl ureas as antagonists of the CC chemokine receptor-3 (CCR3) are presented. These compounds displayed potent binding to the receptor as well as functional antagonism of eotaxin-elicited effects on eosinophils. 相似文献
59.
60.
Effect of inhibiting nitric oxide production on mouse preimplantation embryo development and metabolism 总被引:2,自引:0,他引:2
Nitric oxide (NO) is a free radical that functions as a cell signaling molecule but at high concentrations can be toxic. It is formed from arginine, which is consumed by the mouse blastocyst, but its effect on early embryo development has been little studied. In this study, the role of NO in mouse preimplantation development has been examined in terms of developmental rate and oxidative metabolism. Zygotes were cultured in one of four media; potassium simplex optimization medium (KSOM), KSOM with amino acids (KSOMaa), KSOM without glutamine (KSOM-glut), or KSOM with 0.5 mM arginine (KSOMarg) +/- l-NAME (a specific inhibitor of NO production). End points were Day 4 blastocyst rates, cell counts determined using bisbenzimide and oxygen consumption. In KSOM and KSOM-glut, the blastocyst rate was decreased by 1 mM l-NAME from 50.2% +/- 3.1% and 37.4% +/- 4.5% to 6% +/- 3% and 0%, respectively. In KSOMaa, cavitation rates were unaltered but the blastocysts contained fewer cells (P < 0.001). Blastocysts cultured in KSOM and KSOM-glut consumed significantly more oxygen than those cultured in KSOMaa (P < 0.001 and P < 0.05, respectively). However, the addition of 0.1 mM or 1 mM l-NAME to KSOMaa significantly increased the amount of oxygen consumed (P < 0.05 and P < 0.001, respectively). The data suggest a physiological role for NO in mouse preimplantation metabolism and development. One possibility is that NO may limit oxygen consumption at the blastocyst stage at the level of mitochondrial cytochrome c oxidase. 相似文献