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1.
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
2.
3‐Aminoazetidin‐2‐one Derivatives as N‐Acylethanolamine Acid Amidase (NAAA) Inhibitors Suitable for Systemic Administration 下载免费PDF全文
Dr. Annalisa Fiasella Dr. Andrea Nuzzi Dr. Maria Summa Dr. Andrea Armirotti Dr. Glauco Tarozzo Prof. Giorgio Tarzia Prof. Marco Mor Dr. Fabio Bertozzi Dr. Tiziano Bandiera Prof. Daniele Piomelli 《ChemMedChem》2014,9(7):1602-1614
N‐Acylethanolamine acid amidase (NAAA) is a cysteine hydrolase that catalyzes the hydrolysis of endogenous lipid mediators such as palmitoylethanolamide (PEA). PEA has been shown to exert anti‐inflammatory and antinociceptive effects in animals by engaging peroxisome proliferator‐activated receptor α (PPAR‐α). Thus, preventing PEA degradation by inhibiting NAAA may provide a novel approach for the treatment of pain and inflammatory states. Recently, 3‐aminooxetan‐2‐one compounds were identified as a class of highly potent NAAA inhibitors. The utility of these compounds is limited, however, by their low chemical and plasma stabilities. In the present study, we synthesized and tested a series of N‐(2‐oxoazetidin‐3‐yl)amides as a novel class of NAAA inhibitors with good potency and improved physicochemical properties, suitable for systemic administration. Moreover, we elucidated the main structural features of 3‐aminoazetidin‐2‐one derivatives that are critical for NAAA inhibition. 相似文献
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Prof. Silvia Rivara Dr. Daniele Pala Dr. Alessio Lodola Prof. Marco Mor Dr. Valeria Lucini Dr. Silvana Dugnani Prof. Francesco Scaglione Dr. Annalida Bedini Dr. Simone Lucarini Prof. Giorgio Tarzia Prof. Gilberto Spadoni 《ChemMedChem》2012,7(11):1954-1964
The design of compounds selective for the MT1 melatonin receptor is still a challenging task owing to the limited knowledge of the structural features conferring selectivity for the MT1 subtype, and only few selective compounds have been reported so far. N‐(Anilinoalkyl)amides are a versatile class of melatonin receptor ligands that include nonselective MT1/MT2 agonists and MT2‐selective antagonists. We synthesized a new series of N‐(anilinoalkyl)amides bearing 3‐arylalkyloxy or 3‐alkyloxy substituents at the aniline ring, looking for new potent and MT1‐selective ligands. To evaluate the effect of substituent size and shape on binding affinity and intrinsic activity, both flexible and conformationally constrained derivatives were prepared. The phenylbutyloxy substituent gave the best result, providing the partial agonist 4 a , which was endowed with high MT1 binding affinity (pKi=8.93) and 78‐fold selectivity for the MT1 receptor. To investigate the molecular basis for agonist recognition, and to explain the role of the 3‐arylalkyloxy substituent, we built a homology model of the MT1 receptor based on the β2 adrenergic receptor crystal structure in its activated state. A binding mode for MT1 agonists is proposed, as well as a hypothesis regarding the receptor structural features responsible for MT1 selectivity of compounds with lipophilic arylalkyloxy substituents. 相似文献
4.
Ilza K. Pajeva Prof. Dr. Christoph Globisch Dr. Michael Wiese Prof. Dr. 《ChemMedChem》2009,4(11):1883-1896
Quinazolinones, indolo‐ and pyrrolopyrimidines with inhibitory effects toward ABCB1 (P‐gp) and ABCC1 (MRP1) transporters were studied by pharmacophore modeling, docking, and 3D QSAR to describe the binding preferences of the proteins. The pharmacophore overlays between dual and/or highly selective inhibitors point to binding sites of different topology and physiochemical properties for MRP1 and P‐gp. Docking of selective inhibitors into the P‐gp binding cavity by the use of a structural model based on the recently resolved P‐gp structure confirms the P‐gp pharmacophore features identified, and reveals the interactions of some functional groups and atoms in the structures with particular protein residues. The 3D QSAR analysis of the dual‐effect inhibitors allows satisfactory prediction of the selectivity index of the compounds and outlines electrostatics as most important for selectivity. The results from the combined modeling approach complement each other and could improve our understanding of the protein–ligand interactions involved, and could aid in the development of highly selective and potent inhibitors of P‐gp and MRP1. 相似文献
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Federica Vacondio Dr. Claudia Silva Prof. Alessio Lodola Dr. Alessandro Fioni Dr. Silvia Rivara Prof. Andrea Duranti Dr. Andrea Tontini Dr. Silvano Sanchini Dr. Jason R. Clapper Dr. Daniele Piomelli Prof. Marco Mor Prof. Giorgio Tarzia Prof. 《ChemMedChem》2009,4(9):1495-1504
Cyclohexylcarbamic acid aryl esters are a class of fatty acid amide hydrolase (FAAH) inhibitors, which includes the reference compound URB597. The reactivity of their carbamate fragment is involved in pharmacological activity and may affect their pharmacokinetic and toxicological properties. We conducted in vitro stability experiments in chemical and biological environments to investigate the structure–stability relationships in this class of compounds. The results show that electrophilicity of the carbamate influences chemical stability, as suggested by the relation between the rate constant of alkaline hydrolysis (log kpH9) and the energy of the lowest unoccupied molecular orbital (LUMO). Introduction of small electron‐donor substituents at conjugated positions of the O‐aryl moiety increased the overall hydrolytic stability of the carbamate group without affecting FAAH inhibitory potency, whereas peripheral non‐conjugated hydrophilic groups, which favor FAAH recognition, helped decrease oxidative metabolism in the liver. 相似文献
7.
O‐(Triazolyl)methyl Carbamates as a Novel and Potent Class of Fatty Acid Amide Hydrolase (FAAH) Inhibitors 下载免费PDF全文
Dr. Giampiero Colombano Clara Albani Dr. Giuliana Ottonello Dr. Alison Ribeiro Dr. Rita Scarpelli Dr. Glauco Tarozzo Jennifer Daglian Dr. Kwang‐Mook Jung Prof. Daniele Piomelli Dr. Tiziano Bandiera 《ChemMedChem》2015,10(2):380-395
Inhibition of fatty acid amide hydrolase (FAAH) activity is under investigation as a valuable strategy for the treatment of several disorders, including pain and drug addiction. A number of potent FAAH inhibitors belonging to different chemical classes have been disclosed to date; O‐aryl carbamates are one of the most representative families. In the search for novel FAAH inhibitors, a series of O‐(1,2,3‐triazol‐4‐yl)methyl carbamate derivatives were designed and synthesized exploiting a copper‐ catalyzed [3+2] cycloaddition reaction between azides and alkynes (click chemistry). Exploration of the structure–activity relationships within this new class of compounds identified potent inhibitors of both rat and human FAAH with IC50 values in the single‐digit nanomolar range. In addition, these derivatives showed improved stability in rat plasma and kinetic solubility in buffer with respect to the lead compound. Based on the results of the study, the novel analogues identified can be considered to be promising starting point for the development of new FAAH inhibitors with improved drug‐like properties. 相似文献
8.
Jun Young Kim Ji Won Lee Young Soo Kim Yuno Lee Dr. Young Bae Ryu Songmi Kim Hyung Won Ryu Marcus J. Curtis‐Long Prof. Dr. Keun Woo Lee Dr. Woo Song Lee Prof. Dr. Ki Hun Park 《Chembiochem : a European journal of chemical biology》2010,11(15):2125-2131
Competitive glycosidase inhibitors are generally sugar mimics that are costly and tedious to obtain because they require challenging and elongated chemical synthesis, which must be stereo‐ and regiocontrolled. Here, we show that readily accessible achiral (E)‐1‐phenyl‐3‐(4‐strylphenyl)ureas are potent competitive α‐glucosidase inhibitors. A systematic synthesis study shows that the 1‐phenyl moiety on the urea is critical for ensuring competitive inhibition, and substituents on both terminal phenyl groups contribute to inhibition potency. The most potent inhibitor, compound 12 (IC50=8.4 μM , Ki=3.2 μM ), manifested a simple slow‐binding inhibition profile for α‐glucosidase with the kinetic parameters k3=0.005256 μM ?1 min?1, k4=0.003024 min?1, and ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$ =0.5753 μM . 相似文献
9.
N‐Myristoyltransferase (NMT) is a cytosolic monomeric enzyme present in eukaryotes such as fungi and protozoa, but is not found in prokaryotes. The attachment of a 14‐carbon saturated fatty acid, myristate, from myristoyl‐CoA (14:0 CoA) to the N‐terminal glycine residue in a specific set of cellular proteins is commonly called protein N‐myristoylation. The myristoylation reaction catalyzed by the enzyme myristoyl CoA:NMT is both necessary for the growth of various organisms and conclusive for cellular proliferation. Therefore, NMT has been identified as a novel and promising target for antifungal, antiparasitic, and anticancer agents, and a large number of potent NMT inhibitors with antifungal, antiparasitic, and anticancer activities have been reported. Herein we describe recent advances in the discovery of NMT inhibitors. We introduce not only the functions of NMT, but also some representative natural and synthetic inhibitors, with a focus on their biological activity, selectivity, and structure–activity relationship (SAR) information. In particular, inspiration from NMT inhibitor structures and the future direction of these compounds are highlighted. 相似文献
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The sodium iodide symporter (NIS) is responsible for the accumulation of iodide in the thyroid gland. This transport process is involved in numerous thyroid dysfunctions and is the basis for human contamination in the case of exposure to radioactive iodine species. 4‐Aryl‐3,4‐dihydropyrimidin‐2(1H)‐ones were recently discovered by high‐throughput screening as the first NIS inhibitors. Described herein are the synthesis and evaluation of 115 derivatives with structural modifications at five key positions on the pyrimidone core. This study provides extensive structure–activity relationships for this new class of inhibitors that will serve as a basis for further development of compounds with in vivo efficacy and adequate pharmacokinetic properties. In addition, the SAR investigation provided a more potent compound, which exhibits an IC50 value of 3.2 nM in a rat thyroid cell line (FRTL5). 相似文献
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Li‐Mei Gao Dr. Sheng Tang Dr. Yan‐Xiang Wang Dr. Rong‐Mei Gao Dr. Xin Zhang Dr. Zong‐Gen Peng Jian‐Rui Li Prof. Jian‐Dong Jiang Prof. Yu‐Huan Li Prof. Dan‐Qing Song 《ChemMedChem》2013,8(9):1545-1553
A series of novel N‐substituted sophocarpinic acid derivatives was designed, synthesized, and evaluated for their anti‐enteroviral activities against coxsackievirus type B3 (CVB3) and coxsackievirus type B6 (CVB6) in Vero cells. Structure–activity relationship analysis revealed that the introduction of a benzenesulfonyl moiety on the 12‐nitrogen atom in (E)‐β,γ‐sophocarpinic acid might significantly enhance anti‐CVB3 activity. Among the derivatives, (E)‐12‐N‐(m‐cyanobenzenesulfonyl)‐β,γ‐sophocarpinic acid ( 11 m ), possessing a meta‐cyanobenzenesulfonyl group, exhibited potent activity against CVB3 with a selectivity index (SI) of 107. Furthermore, compound 11 m also showed a good oral pharmacokinetic profile, with an AUC value of 7.29 μM h?1 in rats, and good safety through the oral route in mice, with an LD50 value of >1000 mg kg?1; these values suggest a druggable characteristic. Therefore, compound 11 m was selected for further investigation as a promising CVB3 inhibitor. We consider (E)‐β,γ‐N‐(benzenesulfonyl)sophocarpinic acids to be a novel class of anti‐CVB3 agents. 相似文献
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Design,Synthesis, and Biological Evaluation of 1,3‐Diarylpropenones as Dual Inhibitors of HIV‐1 Reverse Transcriptase 下载免费PDF全文
Dr. Rita Meleddu Dr. Valeria Cannas Dr. Simona Distinto Dr. Giorgia Sarais Dr. Claudia Del Vecchio Dr. Francesca Esposito Dr. Giulia Bianco Dr. Angela Corona Dr. Filippo Cottiglia Prof. Stefano Alcaro Prof. Cristina Parolin Dr. Anna Artese Dr. Daniela Scalise Prof. Massimo Fresta Dr. Antonella Arridu Dr. Francesco Ortuso Prof. Elias Maccioni Prof. Enzo Tramontano 《ChemMedChem》2014,9(8):1869-1879
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Synthesis and Biological Evaluation of Papain‐Family Cathepsin L‐Like Cysteine Protease Inhibitors Containing a 1,4‐Benzodiazepine Scaffold as Antiprotozoal Agents 下载免费PDF全文
Dr. Roberta Ettari Dr. Andrea Pinto Dr. Lucia Tamborini Dr. Ilenia C. Angelo Prof. Silvana Grasso Prof. Maria Zappalà Dr. Natale Capodicasa Dr. Laura Yzeiraj Dr. Esther Gruber Dr. Makoah N. Aminake Dr. Gabriele Pradel Prof. Tanja Schirmeister Prof. Carlo De Micheli Prof. Paola Conti 《ChemMedChem》2014,9(8):1817-1825
Novel papain‐family cathepsin L‐like cysteine protease inhibitors endowed with antitrypanosomal and antimalarial activity were developed, through an optimization study of previously developed inhibitors. In the present work, we studied the structure–activity relationships of these derivatives, with the aim to develop new analogues with a simplified and more synthetically accessible structure and with improved antiparasitic activity. The structure of the model compounds was significantly simplified by modifying or even eliminating the side chain appended at the C3 atom of the benzodiazepine scaffold. In addition, a simple methylene spacer of appropriate length was inserted between the benzodiazepine ring and the 3‐bromoisoxazoline moiety. Several rhodesain and falcipain‐2 inhibitors displaying single‐digit micromolar or sub‐micromolar antiparasitic activity against one or both parasites were identified, with activities that were one order of magnitude more potent than the model compounds. 相似文献
14.
Tarzia G Duranti A Gatti G Piersanti G Tontini A Rivara S Lodola A Plazzi PV Mor M Kathuria S Piomelli D 《ChemMedChem》2006,1(1):130-139
Fatty acid amide hydrolase (FAAH) is a serine hydrolase that catalyzes the intracellular hydrolysis of fatty acid ethanolamides such as anandamide and oleoylethanolamide. Targeting this enzyme may have important therapeutic potentials owing to the multiple physiological roles of these amides. Cyclohexylcarbamic acid biphenyl-3-yl ester (URB524) was one of the most promising FAAH inhibitors so far described. We report the modulation of the electronic and steric features of the proximal phenyl ring of this compound by introducing a series of substituents at the ortho and para positions. pIC50 values were found to correlate with molecular features thought to be involved in the recognition step such as steric hindrance and hydrogen-bonding ability. Derivatives with small polar groups at the para position of the proximal phenyl ring were slightly better FAAH inhibitors than the parent compound URB524. 相似文献
15.
1‐(1H‐Indol‐3‐yl)ethanamine Derivatives as Potent Staphylococcus aureus NorA Efflux Pump Inhibitors 下载免费PDF全文
Dr. Arnaud Hequet Dr. Olga N. Burchak Dr. Matthieu Jeanty Dr. Xavier Guinchard Dr. Emmanuelle Le Pihive Dr. Laure Maigre Pascale Bouhours Prof. Dominique Schneider Prof. Max Maurin Dr. Jean‐Marc Paris Dr. Jean‐Noël Denis Prof. Dr. Claude Jolivalt 《ChemMedChem》2014,9(7):1534-1545
The synthesis of 37 1‐(1H‐indol‐3‐yl)ethanamine derivatives, including 12 new compounds, was achieved through a series of simple and efficient chemical modifications. These indole derivatives displayed modest or no intrinsic anti‐staphylococcal activity. By contrast, several of the compounds restored, in a concentration‐dependent manner, the antibacterial activity of ciprofloxacin against Staphylococcus aureus strains that were resistant to fluoroquinolones due to overexpression of the NorA efflux pump. Structure–activity relationships studies revealed that the indolic aldonitrones halogenated at position 5 of the indole core were the most efficient inhibitors of the S. aureus NorA efflux pump. Among the compounds, (Z)‐N‐benzylidene‐2‐(tert‐butoxycarbonylamino)‐1‐(5‐iodo‐1H‐indol‐3‐yl)ethanamine oxide led to a fourfold decrease of the ciprofloxacin minimum inhibitory concentration against the SA‐1199B strain when used at a concentration of 0.5 mg L ?1. To the best of our knowledge, this activity is the highest reported to date for an indolic NorA inhibitor. In addition, a new antibacterial compound, tert‐butyl (2‐(3‐hydroxyureido)‐2‐(1H‐indol‐3‐yl)ethyl)carbamate, which is not toxic for human cells, was also found. 相似文献
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Dr. Teemu Haikarainen Dr. Jarkko Koivunen Mohit Narwal Harikanth Venkannagari Ezeogo Obaji Päivi Joensuu Prof. Taina Pihlajaniemi Dr. Lari Lehtiö 《ChemMedChem》2013,8(12):1978-1985
Human tankyrases are attractive drug targets, especially for the treatment of cancer. We identified a set of highly potent tankyrase inhibitors based on a 2‐phenyl‐3,4‐dihydroquinazolin‐4‐one scaffold. Substitutions at the para position of the scaffold′s phenyl group were evaluated as a strategy to increase potency and improve selectivity. The best compounds displayed single‐digit nanomolar potencies, and profiling against several human diphtheria‐toxin‐like ADP‐ribosyltransferases revealed that a subset of these compounds are highly selective tankyrase inhibitors. The compounds also effectively inhibit Wnt signaling in HEK293 cells. The binding mode of all inhibitors was studied by protein X‐ray crystallography. This allowed us to establish a structural basis for the development of highly potent and selective tankyrase inhibitors based on the 2‐phenyl‐3,4‐dihydroquinazolin‐4‐one scaffold and outline a rational approach to the modification of other inhibitor scaffolds that bind to the nicotinamide site of the catalytic domain. 相似文献
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Design and Synthesis of A‐Ring Simplified Pyripyropene A Analogues as Potent and Selective Synthetic SOAT2 Inhibitors 下载免费PDF全文
Dr. Masaki Ohtawa Shiho Arima Naoki Ichida Tomiaki Terayama Hironao Ohno Takaya Yamazaki Dr. Taichi Ohshiro Noriko Sato Prof. Satoshi Omura Prof. Hiroshi Tomoda Prof. Tohru Nagamitsu 《ChemMedChem》2018,13(5):411-421
Currently, pyripyropene A, which is isolated from the culture broth of Aspergillus fumigatus FO‐1289, is the only compound known to strongly and selectively inhibit the isozyme sterol O‐acyltransferase 2 (SOAT2). To aid in the development of new cholesterol‐lowering or anti‐atherosclerotic agents, new A‐ring simplified pyripyropene A analogues have been designed and synthesized based on total synthesis, and the results of structure–activity relationship studies of pyripyropene A. Among the analogues, two A‐ring simplified pyripyropene A analogues exhibited equally efficient SOAT2 inhibitory activity to that of natural pyripyropene A. These new analogues are the most potent and selective SOAT2 inhibitors to be used as synthetic compounds and attractive seed compounds for the development of drug for dyslipidemia, including atherosclerotic disease and steatosis. 相似文献
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