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71.
Evaluation of (4‐Arylpiperidin‐1‐yl)cyclopentanecarboxamides As High‐Affinity and Long‐Residence‐Time Antagonists for the CCR2 Receptor
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Dr. Maris Vilums Dr. Annelien J. M. Zweemer Arian Dilanchian Jacobus P. D. van Veldhoven Henk de Vries Dr. Johannes Brussee Dr. John Saunders Dr. Dean Stamos Dr. Laura H. Heitman Prof. Adriaan P. IJzerman 《ChemMedChem》2015,10(7):1249-1258
Animal models suggest that the chemokine ligand 2/CC‐chemokine receptor 2 (CCL2/CCR2) axis plays an important role in the development of inflammatory diseases. However, CCR2 antagonists have failed in clinical trials because of a lack of efficacy. We previously described a new approach for the design of CCR2 antagonists by the use of structure–kinetics relationships (SKRs). Herein we report new findings on the structure–affinity relationships (SARs) and SKRs of the reference compound MK‐0483, its diastereomers, and its structural analogues as CCR2 antagonists. The SARs of the 4‐arylpiperidine group suggest that lipophilic hydrogen‐bond‐accepting substituents at the 3‐position are favorable. However, the SKRs suggest that a lipophilic group with a certain size is desired [e.g., 3‐Br: Ki=2.8 nM , residence time (tres)=243 min; 3‐iPr: Ki=3.6 nM , tres=266 min]. Alternatively, additional substituents and further optimization of the molecule, while keeping a carboxylic acid at the 3‐position, can also prolong tres; this was most prominently observed in MK‐0483 (Ki=1.2 nM , tres=724 min) and a close analogue (Ki=7.8 nM ) with a short residence time. 相似文献
72.
A number of toxinogenic fungal species, particularly producers of tremorgenic mycotoxins, have been isolated from traditional fermented meats. Tremorgenic mycotoxins are a group of fungal metabolites known to act on the central nervous system, causing sustained tremors, convulsions, and death in animals. However, the mode of action of these mycotoxins has not been elucidated in detail, and their genotoxic capacity has hardly been investigated. Because genotoxicity is one of the most prominent toxicological end points in food safety testing, we assessed the genotoxicity of five tremorgenic mycotoxins (fumitremorgen B, paxilline, penitrem A, verrucosidin, and verruculogen) associated with molds found in fermented meats. The mycotoxins were tested in two short-term in vitro assays with the use of different genotoxic end points in different phylogenetic systems (the Ames Salmonella/mammalian-microsome assay and the single-cell gel electrophoresis assay of human lymphocytes). According to the results obtained in this study, all of the investigated mycotoxins except penitrem A exhibited a certain degree of genotoxicity. Verrucosidin appeared to have the highest toxic potential, testing positive in both assays. Verruculogen tested positive in the Salmonella/mammalian-microsome assay, and paxilline and fumitremorgen B caused DNA damage in human lymphocytes. The use of fungal starter cultures to avoid tremorgen contamination in fermented meats is recommended. 相似文献
73.
In recent years it has become evident that various synthesis problems known from linear system theory can also be solved for nonlinear control systems by using differential geometric methods. The purpose of this paper is to use this mathematical framework for giving a preliminary account on the notion of right-invertibility of a nonlinear system. This concept, which is of importance in several tracking problems, requires a Taylor-series expansion of the output function. We will also show that there is an appealing geometric interpretation of the lower-order terms in this series expansion. In this way a function that can occur as output function of a nonlinear system is partly described by specifying its k-jet. 相似文献
74.
Assessing footwear slip-resistance is critical to preventing slip and fall accidents. The STM 603 (SATRA Technology) is commonly used to assess footwear friction but its ability to predict human slips while walking is unclear. This study assessed this apparatus’ ability to predict slips across footwear designs and to determine if modifying the test parameters alters predictions. The available coefficient of friction (ACOF) was measured with the device for nine different footwear designs using 12 testing conditions with varying vertical force, speed and shoe angle. The occurrence of slipping and the required coefficient of friction was quantified from human gait data including 124 exposures to liquid contaminants. ACOF values varied across the test conditions leading to different slip prediction models. Generally, a steeper shoe angle (13°) and higher vertical forces (400 or 500?N) modestly improved predictions of slipping. This study can potentially guide improvements in predictive test conditions for this device.
Practitioner Summary: Frictional measures by the STM603 (SATRA Technology) were able to predict human slips under liquid contaminant conditions. Test parameters did have an influence on the measurements. An increased shoe-floor testing angle resulted in better slip predictions than test methods specified in the ASTM F2913 standard. 相似文献
75.
The thickness, the refractive index, and the optical anisotropy of thin sulfonated poly(ether ether ketone) films, prepared by spin-coating or solvent deposition, have been investigated with spectroscopic ellipsometry. For not too high polymer concentrations (≤5 wt%) and not too low spin speeds (≥2000 rpm), the thicknesses of the films agree well with the scaling predicted by the model of Meyerhofer, when methanol or ethanol are used as solvent. The films exhibit uniaxial optical anisotropy with a higher in-plane refractive index, indicating a preferred orientation of the polymer chains in this in-plane direction. The radial shear forces that occur during the spin-coating process do not affect the refractive index and the extent of anisotropy. The anisotropy is due to internal stresses within the thin confined polymer film that are associated with the preferred orientations of the polymer chains. The internal stresses are reduced in the presence of a plasticizer, such as water or an organic solvent, and increase to their original value upon removal of such a plasticizer. 相似文献
76.
Antonio Fonseca Sander Reijerkerk Kitty Nijmeijer Joseph Delhalle 《Desalination》2010,250(3):1150-1154
The cutting and functionalization of carbon nanotubes is described, applying a single-step ball-mill based process. Very short carbon nanotubes bearing primary amine functions were produced, characterized and incorporated in polymeric membranes. The gas separation performance of the composite membranes was tested. 相似文献
77.
The problem of local stabilizability of locally controllable nonlinear systems is considered. It is well known that, contrary to the linear case, local controllability does not necessarily imply stabilizability. A class of nonlinear systems for which local controllability implies local asymptotic stabilizability using continuous static-state feedback is described, as for this class of systems the well-known Hermes controllability condition is necessary and sufficient for local controllability 相似文献
78.
OBJECTIVE: The life events model was extended to the political arena to enable the comparison of children's adjustment reactions to political stress. The cross-cultural impact of adverse political events on psychological adjustment was examined for two closely matched research samples, Arab and Jewish children and Palestinian and Israeli children. METHOD: All children completed the Political Life Events scale and the Brief Symptom Inventory in their home languages. RESULTS: The hypothesis of a linear relation between adverse events and psychological distress was not confirmed in both studies. In study 1, a direct relation emerged for both Jewish and Arab Israeli children. However, in study 2, when separated by nationality, results revealed opposite trends for each nation. For Israelis there was a linear relation, but for Palestinians there was a consistent inverse relation between increased severity of political life events exposure and distress, both for the global index and for specific symptomatology. CONCLUSION: It is proposed that these cross-cultural results stem from differential mediating coping mechanisms, specifically passive versus active strategies, which intervene between the stressor-adjustment link. The need to address short- and long-term consequences of political stress on children's mental health is discussed. 相似文献
79.
80.
A novel way for anion exchange membrane (AEM) preparation has been investigated, avoiding the use of expensive and toxic chemicals. This new synthetic approach to prepare AEMs was based on the use of a porous polybenzylimidazole membrane as support in which functionalized ILs were introduced and subsequently grafted on the polymer backbone. These new AEMs were prepared and their chemical structures and properties including morphology, thermal stability, and ionic conductivity were characterized. The hydroxyl ionic conductivity of the synthesized membranes can reach values upto 6.62 × 10?3 S cm?1 at 20°C. Although the ionic conductivity is not very high yet, the work shows the strength of the concept. Membrane properties can be easily tailored toward specific applications by choosing the proper chemistry, i.e., porous polymer support, ionic liquid, and method of initiation and polymerization. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013 相似文献