共查询到20条相似文献,搜索用时 15 毫秒
1.
Pang L Kleeb S Lemme K Rabbani S Scharenberg M Zalewski A Schädler F Schwardt O Ernst B 《ChemMedChem》2012,7(8):1404-1422
Urinary tract infections (UTIs) are caused primarily by uropathogenic Escherichia coli (UPEC), which encode filamentous surface‐adhesive organelles called type 1 pili. FimH is located at the tips of these pili. The initial attachment of UPEC to host cells is mediated by the interaction of the carbohydrate recognition domain (CRD) of FimH with oligomannosides on urothelial cells. Blocking these lectins with carbohydrates or analogues thereof prevents bacterial adhesion to host cells and therefore offers a potential therapeutic approach for prevention and/or treatment of UTIs. Although numerous FimH antagonists have been developed so far, few of them meet the requirement for clinical application due to poor pharmacokinetics. Additionally, the binding mode of an antagonist to the CRD of FimH can switch from an in‐docking mode to an out‐docking mode, depending on the structure of the antagonist. In this communication, biphenyl α‐D ‐mannosides were modified to improve their binding affinity, to explore their binding mode, and to optimize their pharmacokinetic properties. The inhibitory potential of the FimH antagonists was measured in a cell‐free competitive binding assay, a cell‐based flow cytometry assay, and by isothermal titration calorimetry. Furthermore, pharmacokinetic properties such as log D, solubility, and membrane permeation were analyzed. As a result, a structure–activity and structure–property relationships were established for a series of biphenyl α‐D ‐mannosides. 相似文献
2.
Dr. Meike Scharenberg Dr. Xiaohua Jiang Lijuan Pang Giulio Navarra Dr. Said Rabbani Dr. Florian Binder Dr. Oliver Schwardt Prof. Dr. Beat Ernst 《ChemMedChem》2014,9(1):78-83
The lectin FimH is terminally expressed on type 1 pili of uropathogenic Escherichia coli (UPEC), which is the main cause of urinary tract infections (UTIs). FimH enables bacterial adhesion to urothelial cells, the initial step of infection. Various mannose derivatives have been shown to antagonize FimH and are therefore considered to be promising therapeutic agents for the treatment of UTIs. As part of the preclinical development process, when the kinetic properties of FimH antagonists were examined by surface plasmon resonance, extremely low dissociation rates (koff) were found, which is uncommon for carbohydrate–lectin interactions. As a consequence, the corresponding half‐lives (t1/2) of the FimH antagonist complexes are above 3.6 h. For a therapeutic application, extended t1/2 values are a prerequisite for success, since the target occupancy time directly influences the in vivo drug efficacy. The long t1/2 value of the tested FimH antagonists further confirms their drug‐like properties and their high therapeutic potential. 相似文献
3.
4.
5.
6.
7.
8.
9.
Inside Cover: Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex (ChemMedChem 4/2014) 下载免费PDF全文
Dr. Eric Jnoff Dr. Claudia Albrecht Dr. John J. Barker Dr. Oliver Barker Dr. Edward Beaumont Dr. Steven Bromidge Dr. Frederick Brookfield Dr. Mark Brooks Dr. Christian Bubert Dr. Tom Ceska Vincent Corden Dr. Graham Dawson Dr. Stephanie Duclos Dr. Tara Fryatt Dr. Christophe Genicot Dr. Emilie Jigorel Dr. Jason Kwong Rosemary Maghames Innocent Mushi Dr. Richard Pike Dr. Zara A. Sands Dr. Myron A. Smith Dr. Christopher C. Stimson Dr. Jean‐Philippe Courade 《ChemMedChem》2014,9(4):674-674
10.
11.
Raphael Reher Dr. Toni Kühl Suvi Annala Tobias Benkel Desireé Kaufmann Britta Nubbemeyer Justin Patrick Odhiambo Dr. Pascal Heimer Charlotte Anneke Bäuml Dr. Stefan Kehraus Dr. Max Crüsemann Prof. Dr. Evi Kostenis Dr. Daniel Tietze Prof. Dr. Gabriele M. König Prof. Dr. Diana Imhof 《ChemMedChem》2018,13(16):1617-1617
12.
13.
Montakarn Chittchang Dr. Paratchata Batsomboon Somsak Ruchirawat Prof. Dr. Poonsakdi Ploypradith Dr. 《ChemMedChem》2009,4(3):298-298
The inside cover picture shows the structure of lamellarin N as a representative of cytotoxic marine lamellarin alkaloids, together with a potential molecular target, the topoisomerase I–DNA complex. Systematic SAR studies revealed the importance of the substituents for potent cytotoxicity. For more details, see the Full Paper by P. Ploypradith et al. on p. 457 ff.
14.
Synthesis,Structure–Activity Relationship Studies,and ADMET Properties of 3‐Aminocyclohex‐2‐en‐1‐ones as Chemokine Receptor 2 (CXCR2) Antagonists 下载免费PDF全文
Weiyang Dai Dr. Wenmin Chen Dr. Bikash Debnath Prof. Yong Wu Prof. Nouri Neamati 《ChemMedChem》2018,13(9):916-930
Herein we describe the synthesis and structure–activity relationships of 3‐aminocyclohex‐2‐en‐1‐one derivatives as novel chemokine receptor 2 (CXCR2) antagonists. Thirteen out of 44 derivatives were found to inhibit CXCR2 downstream signaling in a Tango assay specific for CXCR2, with IC50 values less than 10 μm . In silico ADMET prediction suggests that all active compounds possess drug‐like properties. None of these compounds show significant cytotoxicity, suggesting their potential application in inflammatory mediated diseases. A structure–activity relationship (SAR) map has been generated to gain better understanding of their binding mechanism to guide further optimization of these new CXCR2 antagonists. 相似文献
15.
16.
Sylvain Petit Yann Duroc Dr. Valéry Larue Dr. Carmela Giglione Dr. Carole Léon Dr. Coralie Soulama Dr. Alexis Denis Dr. Frédéric Dardel Prof. Thierry Meinnel Dr. Isabelle Artaud Dr. 《ChemMedChem》2009,4(2):133-133
The cover picture shows a “reverse” indole derivative in complex with Bacillus stearothermophilus peptide deformylase (PDF). This compound was selected from a structure–activity relationship study as a potent inhibitor of bacterial PDFs and shows antibacterial activity toward Bacillus subtilis as well as other pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. For more details, see the Full Paper by I. Artaud et al. on p. 261 ff.
17.
18.
Dr. Renée Roodbeen Berit Paaske Longguang Jiang Dr. Jan K. Jensen Anni Christensen Dr. Jakob T. Nielsen Prof. Dr. Mingdong Huang Prof. Frans A. A. Mulder Prof. Dr. Niels Chr. Nielsen Prof. Dr. Peter A. Andreasen Prof. Dr. Knud J. Jensen 《Chembiochem : a European journal of chemical biology》2013,14(16):2062-2062
19.
20.
2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines and Derived Novel Heterocycles: Syntheses and Structure–Activity Relationships of Potent Adenosine Receptor Antagonists 下载免费PDF全文
Dr. Joachim C. Burbiel Dr. Wadih Ghattas Dr. Petra Küppers Dr. Meryem Köse Dr. Svenja Lacher Dr. Anna‐Maria Herzner Dr. Rajan Subramanian Kombu Prof. Dr. Raghuram Rao Akkinepally Dr. Jörg Hockemeyer Prof. Dr. Christa E. Müller 《ChemMedChem》2016,11(20):2272-2286
2‐Amino[1,2,4]triazolo[1,5‐c]quinazolines were identified as potent adenosine receptor (AR) antagonists. Synthetic strategies were devised to gain access to a broad range of derivatives including novel polyheterocyclic compounds. Potent and selective A3AR antagonists were discovered, including 3,5‐diphenyl[1,2,4]triazolo[4,3‐c]quinazoline ( 17 , Ki human A3AR 1.16 nm ) and 5′‐phenyl‐1,2‐dihydro‐3′H‐spiro[indole‐3,2′‐[1,2,4]triazolo[1,5‐c]quinazolin]‐2‐one ( 20 , Ki human A3AR 6.94 nm ). In addition, multitarget antagonists were obtained, such as the dual A1/A3 antagonist 2,5‐diphenyl[1,2,4]triazolo[1,5‐c]quinazoline ( 13 b , Ki human A1AR 51.6 nm , human A3AR 11.1 nm ), and the balanced pan‐AR antagonists 5‐(2‐thienyl)[1,2,4]triazolo[1,5‐c]quinazolin‐2‐amine ( 11 c , Ki human A1AR 131 nm , A2AAR 32.7 nm , A2BAR 150 nm , A3AR 47.5 nm ) and 9‐bromo‐5‐phenyl[1,2,4]triazolo[1,5‐c]quinazolin‐2‐amine ( 11 q , Ki human A1AR 67.7 nm , A2AAR 13.6 nm , A2BAR 75.0 nm , A3AR 703 nm ). In many cases, significantly different affinities for human and rat receptors were observed, which emphasizes the need for caution in extrapolating conclusions between different species. 相似文献