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排序方式: 共有3047条查询结果,搜索用时 15 毫秒
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Steffen Vojacek Lukas Schulig Nathalie Wössner Norman Geist Prof. Dr. Walter Langel Prof. Dr. Manfred Jung Prof. Dr. Dennis Schade Prof. Dr. Andreas Link 《ChemMedChem》2019,14(8):853-864
Indoles are privileged structures in medicinal and bioorganic chemistry that are particularly well suited to serve as platforms for diversity. Among many other therapeutic areas, the indole scaffold has been used to design aromatic compounds useful to interfere with enzymes engaged in the regulation of substrate acylation status, such as sirtuins. However, the planarity of the indole ring is not necessarily optimal for all target enzymes, especially when functionalization with aromatic side chains is required. Replacement of flat scaffolds by nonplanar molecular cores dominated by sp3 hybridization is a common strategy to avoid the disadvantages associated with poor solubility and high promiscuity, while covering less-well-explored areas of chemical space. Thus, we synthesized fragment-like tetrahydroindoles suitable for fragment-based drug discovery as well as a well-characterized small library intended as multipurpose screening compounds. For proof of principle, these compounds were screened against sirtuins 1–3, enzymes known to be addressable by indoles. We found that 2,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamides are potent and selective SIRT2 inhibitors. Compound 16 t displayed an IC50 value of 0.98 μm and could serve as exquisite starting point for hit-to-lead profiling. 相似文献
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Dr. Li Di Prof. Per Artursson Dr. Alex Avdeef Prof. Leslie Z. Benet Prof. J. Brian Houston Dr. Manfred Kansy Edward H. Kerns Prof. Hans Lennernäs Dr. Dennis A. Smith Prof. Kiyohiko Sugano 《ChemMedChem》2020,15(20):1862-1874
Passive permeability is a key property in drug disposition and delivery. It is critical for gastrointestinal absorption, brain penetration, renal reabsorption, defining clearance mechanisms and drug-drug interactions. Passive diffusion rate is translatable across tissues and animal species, while the extent of absorption is dependent on drug properties, as well as in vivo physiology/pathophysiology. Design principles have been developed to guide medicinal chemistry to enhance absorption, which combine the balance of aqueous solubility, permeability and the sometimes unfavorable compound characteristic demanded by the target. Permeability assays have been implemented that enable rapid development of structure-permeability relationships for absorption improvement. Future advances in assay development to reduce nonspecific binding and improve mass balance will enable more accurately measurement of passive permeability. Design principles that integrate potency, selectivity, passive permeability and other ADMET properties facilitate rapid advancement of successful drug candidates to patients. 相似文献
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Diese Recherche zeigt, dass sich die Bedeutung, die dem Thema RFID in den Medien und der ?ffentlichen Diskussion derzeit beigemessen
wird, auch in der Anzahl der im Internet zu findenden Seiten niederschl?gt. Dabei bewegt sich die Qualit?t der betrachteten
Angebote überwiegend auf einem hohen Niveau, was vor allem auf Seiten der kommerziellen Anbieter nicht weiter verwundert,
da es sich bei RFID doch um einen zunehmend st?rker umk?mpften Markt handelt, auf dem es hei?t, potenzielle Kunden für sich
zu akquirieren. Es darf mit Spannung erwartet werden, wie sich das Informationsangebot wandelt, wenn tats?chlich das prognostizierte
exponentielle Wachstum des RFID-Marktes eintritt. 相似文献
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The curing of diglycidyl ether of bisphenol A (DGEBA) with 2,6-dimethylol-p-cresol modified by hexahydrophthalic acid anhydride was investigated and compared with the analogous in situ curing of DGEBA, hexahydrophthalic acid anhydride and 2,6-dimethylol-p-cresol. The chemical reactions were investigated by means of titration and different spectroscopic and chromatographic methods. It was examined whether the less complicated and therefore cheaper in situ reaction delivers postcured products with equal or better properties. Furthermore, it was investigated whether the results are similar using technical phenolic hardeners. 相似文献
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A multilayer theory has been developed for unidirectional/cross-ply unbalanced laminates subjected to surface shear tractions, using the assumption of plane strain. The analytical solution for the stress field in the laminate is obtained and it is shown that the stresses in each layer are in good agreement with the results of a three-dimensional finite element analysis. Approximate formulae for the analytical stresses are also derived for a laminate subjected to an offset distributed force at one end. The accuracy of this solution is shown by comparison with a three-dimensional finite element analysis. 相似文献
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A new sub-class of binding protein-dependent transporter with specificity for a broad range of polar amino acids has been identified by sequence comparison, in Rhizobium leguminosarum, Rhodobacter capsulatus, Escherichia coli and Pseudomonas fluorescens. Southern blotting and PCR analysis has shown that transporters from this new sub-class are widely distributed in Gram-negative bacteria, including, in addition to the above, Citrobacter freundii, Erwinia carotovorum and Rhizobium meliloti. ABC transporters of polar amino acids can be divided into two groups: those with narrow solute specificity and the newly identified sub-class with broad solute specificity. The binding and inner membrane proteins from transporters with a broad solute specificity are larger by approximately 30% than those with a narrow solute specificity. Multiple alignment of the inner membrane proteins from all sequenced polar amino acid transporters indicates there is an N-terminal conserved region that may be involved in solute specificity. A conserved arginine or lysine at residue 30 of this region is changed to glutamate in arginine transporters. Residue 53 also has a strong correlation with the charge on the transported solute, with basic amino acid transporters replacing an aliphatic amino acid at this position with a negatively charged amino acid. The general amino acid permease from R. leguminosarum, which will transport aliphatic as well as basic and acidic amino acids, juxtaposes two prolines at residues 52 and 53 of the N-terminal conserved region. 相似文献
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