共查询到20条相似文献,搜索用时 11 毫秒
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Binding Mode and Structure–Activity Relationships around Direct Inhibitors of the Nrf2–Keap1 Complex 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):699-705
An X‐ray crystal structure of Kelch‐like ECH‐associated protein (Keap1) co‐crystallised with (1S,2R)‐2‐[(1S)‐1‐[(1,3‐dioxo‐2,3‐dihydro‐1H‐isoindol‐2‐yl)methyl]‐1,2,3,4‐tetrahydroisoquinolin‐2‐carbonyl]cyclohexane‐1‐carboxylic acid (compound (S,R,S)‐ 1 a ) was obtained. This X‐ray crystal structure provides breakthrough experimental evidence for the true binding mode of the hit compound (S,R,S)‐ 1 a , as the ligand orientation was found to differ from that of the initial docking model, which was available at the start of the project. Crystallographic elucidation of this binding mode helped to focus and drive the drug design process more effectively and efficiently. 相似文献
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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.
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Modified Peptide Inhibitors of the Keap1–Nrf2 Protein–Protein Interaction Incorporating Unnatural Amino Acids 下载免费PDF全文
Dr. Nikolaos D. Georgakopoulos Dr. Sandeep K. Talapatra Dr. Jemma Gatliff Prof. Frank Kozielski Dr. Geoff Wells 《Chembiochem : a European journal of chemical biology》2018,19(17):1810-1816
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Dr. Xianqi Kong Dr. Dragic Vukomanovic Prof. Kanji Nakatsu Prof. Walter A. Szarek 《ChemMedChem》2015,10(8):1435-1441
Devising ways to up‐ or down‐regulate heme oxygenase activity is attracting much interest as a strategy for the treatment of a variety of disorders. With a view of obtaining compounds that exhibit high potency and selectivity as inhibitors of the heme oxygenase‐2 (HO‐2) isozyme (constitutive) relative to the heme oxygenase‐1 (HO‐1) isozyme (inducible), several 1,2‐disubstituted 1H‐benzimidazoles were designed and synthesized. Specifically, analogues were synthesized in which the C2 substituent was the following: (1H‐imidazol‐1‐yl)methyl, (N‐morpholinyl)methyl, cyclopentylmethyl, cyclohexylmethyl, or (norborn‐2‐yl)methyl. Compounds with the cyclic system in the C2 substituent being a carbocyclic ring, especially cyclohexyl or norborn‐2‐yl, and the N1 substituent being a ring‐substituted benzyl group, especially 4‐chlorobenzyl or 4‐bromobenzyl, best exhibited the target criteria of high potency and selectivity toward inhibition of HO‐2. The new candidates should be useful pharmacological tools and may have therapeutic applications. 相似文献
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Synthesis,Structure–Activity,and Structure–Stability Relationships of 2‐Substituted‐N‐(4‐oxo‐3‐oxetanyl) N‐Acylethanolamine Acid Amidase (NAAA) Inhibitors 下载免费PDF全文
Romina Vitale Dr. Giuliana Ottonello Rita Petracca Sine Mandrup Bertozzi Dr. Stefano Ponzano Dr. Andrea Armirotti Dr. Anna Berteotti Dr. Mauro Dionisi Prof. Andrea Cavalli Prof. Daniele Piomelli Dr. Tiziano Bandiera Dr. Fabio Bertozzi 《ChemMedChem》2014,9(2):323-336
N‐Acylethanolamine acid amidase (NAAA) is a cysteine amidase that preferentially hydrolyzes saturated or monounsaturated fatty acid ethanolamides (FAEs), such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), which are endogenous agonists of nuclear peroxisome proliferator‐activated receptor‐α (PPAR‐α). Compounds that feature an α‐amino‐β‐lactone ring have been identified as potent and selective NAAA inhibitors and have been shown to exert marked anti‐inflammatory effects that are mediated through FAE‐dependent activation of PPAR‐α. We synthesized and tested a series of racemic, diastereomerically pure β‐substituted α‐amino‐β‐lactones, as either carbamate or amide derivatives, investigating the structure–activity and structure–stability relationships (SAR and SSR) following changes in β‐substituent size, relative stereochemistry at the α‐ and β‐positions, and α‐amino functionality. Substituted carbamate derivatives emerged as more active and stable than amide analogues, with the cis configuration being generally preferred for stability. Increased steric bulk at the β‐position negatively affected NAAA inhibitory potency, while improving both chemical and plasma stability. 相似文献
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Cover Picture: Time‐Dependent Diaryl Ether Inhibitors of InhA: Structure–Activity Relationship Studies of Enzyme Inhibition,Antibacterial Activity,and in vivo Efficacy (ChemMedChem 4/2014) 下载免费PDF全文
Dr. Pan Pan Dr. Susan E. Knudson Dr. Gopal R. Bommineni Dr. Huei‐Jiun Li Cheng‐Tsung Lai Dr. Nina Liu Prof. Miguel Garcia‐Diaz Prof. Carlos Simmerling Dr. Sachindra S. Patil Prof. Richard A. Slayden Prof. Peter J. Tonge 《ChemMedChem》2014,9(4):673-673
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Francesc Yraola Dr. Antonio Zorzano Prof. Dr. Fernando Albericio Prof. Dr. Miriam Royo Dr. 《ChemMedChem》2009,4(4):495-503
SSAO/VAP‐1 substrates may be valuable for the treatment or prevention of diabetes mellitus, as they show insulin‐mimetic properties. This review highlights the importance of studying the relevant steric and electronic features in the development of new ligands with better SSAO/VAP‐1 recognition, enhanced selectivity over other amine oxidases, and improved metabolic behavior.
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Dr. Anna Kwiatkowska Frédéric Couture Dr. Christine Levesque Kévin Ly Sophie Beauchemin Roxane Desjardins Prof. Witold Neugebauer Prof. Yves L. Dory Prof. Robert Day 《ChemMedChem》2016,11(3):289-301
PACE4 plays important roles in prostate cancer cell proliferation. The inhibition of this enzyme has been shown to slow prostate cancer progression and is emerging as a promising therapeutic strategy. In previous work, we developed a highly potent and selective PACE4 inhibitor, the multi‐Leu (ML) peptide, an octapeptide with the sequence Ac‐LLLLRVKR‐NH2. Here, with the objective of developing a useful compound for in vivo administration, we investigate the effect of N‐terminal modifications. The inhibitory activity, toxicity, stability, and cell penetration properties of the resulting analogues were studied and compared to the unmodified inhibitor. Our results show that the incorporation of a polyethylene glycol (PEG) moiety leads to a loss of antiproliferative activity, whereas the attachment of a lipid chain preserves or improves it. However, the lipidated peptides are significantly more toxic when compared with their unmodified counterparts. Therefore, the best results were achieved not by the N‐terminal extension but by the protection of both ends with the d ‐Leu residue and 4‐amidinobenzylamide, which yielded the most stable inhibitor, with an excellent activity and toxicity profile. 相似文献
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Claudia Sorbi Dr. Silvia Franchini Dr. Annalisa Tait Prof. Adolfo Prandi Dr. Rossella Gallesi Piero Angeli Prof. Gabriella Marucci Prof. Lorenza Pirona Dr. Elena Poggesi Dr. Livio Brasili Prof. 《ChemMedChem》2009,4(3):393-399
Conformational restriction of naftopidil led to the discovery of a new class of ligands with a 1,3‐dioxolane (1,3‐oxathiolane, 1,3‐dithiolane) structure that bind to α1 adrenoceptor subtypes and 5‐HT1A receptors. Adequate structural modifications address the selectivity toward one or the other receptor system.
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James C. Barrow Dr. Kenneth E. Rittle Phung L. Ngo Harold G. Selnick Dr. Samuel L. Graham Dr. Steven M. Pitzenberger Dr. Georgia B. McGaughey Dennis Colussi Ming‐Tain Lai Dr. Qian Huang Katherine Tugusheva Amy S. Espeseth Dr. Adam J. Simon Dr. Sanjeev K. Munshi Dr. Joseph P. Vacca Dr. 《ChemMedChem》2007,2(7):909-909
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