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排序方式: 共有3006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
3.
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
4.
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
5.
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
6.
H Neudeck M Joncic C Schuster S Bisson R Hildebrandt T Oney B Stiemer H Hopp R Graf 《Canadian Metallurgical Quarterly》1997,37(6):449-458
Nitric oxide (NO) acts as a modulator of neuronal transmission in mature neuronal systems, including the retina. Recently, NO has also been suggested to have a trophic function during development. We examined immunocytochemically the distribution of NO-producing cells in developing and transplanted rabbit retinas. An antibody detecting the neuronal isoform of its biosynthetic enzyme, nitric oxide synthase (NOS), was used on normal developing retinas [starting at embryonic day (E) 15] and on rabbit retinal transplants after various survival times (1-139 days after surgery). Weakly stained cell bodies were first observed in the proximal margin of the neuroblastic layer at E 29. Stained processes projecting towards a developing inner plexiform layer were also visible at this time point. Immunoreactive cells were located at later stages in the innermost part of the inner nuclear layer and in the ganglion cell layer, and are likely to correspond mainly to amacrine cells. NOS-labelled cells were also found in retinal transplants. The first NOS-labelled cells appeared, as in normal developing retinas, in ages corresponding to E 29 and were still detected in transplants corresponding to postnatal day 123. NOS-labelled cells were seen in areas between rosettes, where amacrine cells are located. NOS-labelled processes were at times seen to project for long distances, forming very distinct plexuses. NOS-containing amacrine cells thus appear both in the transplants and in developing retinas in the embryonic stages, long before synaptic function involving these cells can be expected, suggesting a role for NO not only in neuromodulation but also in retinal development. 相似文献
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R Zahn A Vogt K Seidl S Schuster H Gülker KW Heinrich M Gottwik K Neuhaus J Senges 《Canadian Metallurgical Quarterly》1997,86(9):712-721
Balloon angioplasty as the treatment of first choice in the setting of an acute myocardial infarction (AMI) is gaining widespread acceptance because of favourable results from specialised centres concerning high patency rates and low mortality. This study reports the results of angioplasty for AMI at large community hospitals during 1992-1995. 4625 procedures were performed at 68 centres of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhaus?rzte (ALKK). The age of the patients was 60.8 +/- 11.3 years, with 75.1% men. The infarct related artery was the left anterior descendent in 43%, the right coronary artery in 37%, the circumflex artery in 16%, a bypass graft in 2.3% and the left main stem in 1.4% of patients. The success rate (residual stenosis < 50%) of the intervention was 86%. There was a wide range of procedures per centre, with a median of 40 AMI angioplasties per year and centre. The amount of angioplasties for AMI in relation to all angioplasties performed during this period rose from 5.2% in 1992 to 5.9% in 1995 (p = 0.01). Local complications at the puncture site occurred in 3.2%, with the need for a surgical intervention in 1.1% of patients. In 273 (5.9%) of the patients a second angioplasty was performed during the hospital stay. Aortocoronary bypass surgery was performed in 3% of the patients. Hospital mortality was 9.5% (438/4625 patients). The mortality rate remained constant during the years investigated (1992: 10.6%; 1993: 8.6%; 1994: 9.7%; 1995: 9.8%; p = ns). Higher mortality was observed in older patients, patients with multiple vessel disease, the left anterior descending artery or a bypass graft as infarct related artery as well as in patients with failed reperfusion (residual stenoses > 50%). Hospitals with a case load of more than 40 angioplasties for AMI per year showed a lower mortality as compared to the others. In clinical practice at large community hospitals results of angioplasty for AMI concerning mortality, complications and technical success rate are comparable to those of highly specialised centres. The absolute numbers of angioplasties for AMI increased constantly over the years. 相似文献
9.
Qualitative urinalysis methods of monitoring cocaine use may over-detect frequency of use, possibly decreasing the ability of clinical trials to detect effective treatments. Quantitative urinalysis and newly developed criteria for identifying new cocaine use were evaluated as alternative measures of cocaine use. Urine specimens collected in a cocaine dosing study in non-treatment-seeking subjects (n = 5) and a cocaine treatment trial (n = 37) were analyzed for the cocaine metabolite, benzoylecgonine, with qualitative and quantitative methods. Pharmacokinetic criteria ('New Use' rules) were applied to quantitative data to identify occasions of new cocaine use. Results were compared to known cocaine administrations in the laboratory study and to self-reported drug use and qualitative urinalysis for subjects in the clinical trial. New Use criteria correctly identified cocaine administrations in the cocaine dosing study in all but a small number of specimens. In the clinical trial, quantitative urinalysis and estimated New Uses provided more information about patterns and frequency of use than qualitative urinalysis in the different treatment conditions in the clinical trial. Interpretation of quantitative urinalysis with New Use rules appears to be a useful method for monitoring treatment outcome and may be more accurate than traditional qualitative urinalysis in estimating frequency of cocaine use. 相似文献
10.