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排序方式: 共有3446条查询结果,搜索用时 46 毫秒
1.
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
2.
Pablo Hernndez‐Alonso Nerea Becerra‐Toms Christopher Papandreou Mnica Bull Marta Guasch‐Ferr Estefanía Toledo Miguel Ruiz‐Canela Clary B. Clish Dolores Corella Courtney Dennis Amy Deik Dong D. Wang Cristina Razquin Jean‐Philippe Drouin‐Chartier Ramon Estruch Emilio Ros Montserrat Fit Fernando Ars Miquel Fiol Lluís Serra‐Majem Liming Liang Miguel A Martínez‐Gonzlez Frank B Hu Jordi Salas‐Salvad 《Molecular nutrition & food research》2020,64(12)
3.
Corrosion of a salt-coated Ni-superalloy has been studied at 900°C under a wet air and sulfur vapor ambient. The corrosion thickness, after an incubation of ~60 hr, linearly increases with the corrosion time t and the onset of surface spallation occurred at t ≈ 60 hr. The corroded layer consists of a corrosion front dominated by Cr3S4 scales and linear precipitate structures, an inner corrosion layer dominated by Ni3S2 and NiO, and an outer corrosion layer dominated by Al2O3 networks surrounding the Ni3S2 and/or NiO scale structures. The corrosion mechanism is discussed based on the coexistence of H2O, sulfur, and oxygen. 相似文献
4.
Applying γ‐Substituted Prolines in the Foldon Peptide: Polarity Contradicts Preorganization 下载免费PDF全文
Dennis Dietz Dr. Vladimir Kubyshkin Prof. Dr. Nediljko Budisa 《Chembiochem : a European journal of chemical biology》2015,16(3):403-406
Rational choice of chemical modifications to proline residues allows the preorganization principle to be exploited for more stable assembly of the foldon domain as a tag for trimerization. With systematic knowledge of how chemical and steric variations of the ring substituents affect the relative stabilities of exo and endo puckers, the preorganization principle should then be usable in biotechnologically synthesized foldon mutants and applicable for protein tagging elsewhere. 相似文献
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6.
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
7.
Wei-Jen Ting Wei-Wen Kuo Dennis Jine-Yuan Hsieh Yu-Lan Yeh Cecilia-Hsuan Day Ya-Hui Chen Ray-Jade Chen Viswanadha Vijaya Padma Yi-Hsing Chen Chih-Yang Huang 《International journal of molecular sciences》2015,16(10):25881-25896
Obesity is one of the major risk factors for nonalcoholic fatty liver disease (NAFLD), and NAFLD is highly associated with an increased risk of cardiovascular disease (CVD). Scholars have suggested that certain probiotics may significantly impact cardiovascular health, particularly certain Lactobacillus species, such as Lactobacillus reuteri GMNL-263 (Lr263) probiotics, which have been shown to reduce obesity and arteriosclerosis in vivo. In the present study, we examined the potential of heat-killed bacteria to attenuate high fat diet (HFD)-induced hepatic and cardiac damages and the possible underlying mechanism of the positive effects of heat-killed Lr263 oral supplements. Heat-killed Lr263 treatments (625 and 3125 mg/kg-hamster/day) were provided as a daily supplement by oral gavage to HFD-fed hamsters for eight weeks. The results show that heat-killed Lr263 treatments reduce fatty liver syndrome. Moreover, heat-killed Lactobacillus reuteri GMNL-263 supplementation in HFD hamsters also reduced fibrosis in the liver and heart by reducing transforming growth factor β (TGF-β) expression levels. In conclusion, heat-killed Lr263 can reduce lipid metabolic stress in HFD hamsters and decrease the risk of fatty liver and cardiovascular disease. 相似文献
8.
Daniel Stubba Dr. Dennis Bensinger Janika Steinbacher Lilia Proskurjakov Álvaro Salcedo Gómez Dr. Uwe Schmidt Prof. Dr. Stefan Roth Prof. Dr. Katja Schmitz Prof. Dr. Boris Schmidt 《ChemMedChem》2019,14(23):2005-2022
The ubiquitin-proteasome system (UPS) is an established therapeutic target for approved drugs to treat selected hematologic malignancies. While drug discovery targeting the UPS focuses on irreversibly binding epoxyketones and slowly-reversibly binding boronates, optimization of novel covalent-reversibly binding warheads remains largely unattended. We previously reported α-ketoamides to be a promising reversible lead motif, yet the cytotoxic activity required further optimization. This work focuses on the lead optimization of phenoxy-substituted α-ketoamides combining the structure-activity relationships from the primed and the non-primed site of the proteasome β5 subunit. Our optimization strategy is accompanied by molecular modeling, suggesting occupation of P1′ by a 3-phenoxy group to increase β5 inhibition and cytotoxic activity in leukemia cell lines. Key compounds were further profiled for time-dependent inhibition of cellular substrate conversion. Furthermore, the α-ketoamide lead structure 27 does not affect escape response behavior in Danio rerio embryos, in contrast to bortezomib, which suggests increased target specificity. 相似文献
9.
Natural disasters greatly impact the environment of affected societies with often unknown consequences. In this study we examine the impact that the Canterbury Earthquakes of 2010–2011 had on the distribution of alcohol outlets in Christchurch, New Zealand. Specifically, we compare the distribution of both on-site and off-site alcohol outlets pre- (December 2009) and post-earthquake (December 2014) and use spatial regression models to identify whether any neighbourhood-level factors predict the observed redistributions. Overall, the number of alcohol outlets decreased by almost 13% after the Canterbury Earthquakes. However, we found a moderate increase in the clustering of both outlet types of outlets in the post-quake period. Increases in rates of both on-site and off-site alcohol outlets in neighbourhoods were positively associated with the percentage of residents who resided in their neighbourhood < 5 years and with neighbourhood crime rate change, while negative associations were found with percentage population aged between 15 and 29 years. The results suggest that the changing spatial distribution of alcohol outlets in Christchurch was not random but driven, in part, by the emergent demographic composition of neighbourhoods. The significant practical and policy implications of a redistribution of alcohol outlets are outlined providing a tangible link between empirical research and practice in an urban environment plagued with post-disaster spatial and social uncertainties. 相似文献
10.
Nikolas Jürgensmeyer Dennis Osenberg Arnulf Reitze Julia Riese Stefan Lier 《化学,工程师,技术》2020,92(12):1998-2004
For some years now, the process industry has been meeting the challenges of the markets with modular production and logistics concepts. This article presents this development process in the form of a four-stage transformation model. It is shown that the path towards modular production environments can be taken step by step. The motto is “evolution instead of revolution”. First, an overview of the state of the art of modularized production and logistics systems is given. Based on this, the article describes and classifies the four different stages of modularization. 相似文献