共查询到20条相似文献,搜索用时 15 毫秒
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Xiao‐Qing Feng Yong‐Hong Liang Zhao‐Sen Zeng Fen‐Er Chen Prof. Dr. Jan Balzarini Prof. Dr. Christophe Pannecouque Prof. Dr. Erik De Clercq Prof. Dr. 《ChemMedChem》2009,4(2):219-224
A novel series of diarylpyrimidine analogues (DAPYs) featuring a naphthyl moiety at the C4 position were designed, with all compounds exhibiting strong activity against wild‐type HIV‐1.
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The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 1 下载免费PDF全文
Thien Duc Tran Florian Wakenhut Dr. Chris Pickford Stephen Shaw Dr. Mike Westby Caroline Smith‐Burchnell Lesa Watson Michael Paradowski Dr. Jared Milbank Dr. Rebecca A. Brimage Rebecca Halstead Dr. Rebecca Glen Dr. Craig P. Wilson Fiona Adam Duncan Hay Jean‐Yves Chiva Carly Nichols Dr. David C. Blakemore Iain Gardner Satish Dayal Dr. Andrew Pike Rob Webster Dr. David C. Pryde 《ChemMedChem》2014,9(7):1378-1386
Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol–Myers–Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl‐imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)‐1‐((S)‐2‐(4‐(4‐(6‐(2‐((S)‐1‐((methoxycarbonyl)‐L ‐valyl)pyrrolidin‐2‐yl)‐1H‐imidazol‐5‐yl)quinoxalin‐2‐yl)phenyl)‐1H‐imidazol‐2‐yl)pyrrolidin‐1‐yl)‐3‐methyl‐1‐oxobutan‐2‐yl)carbamate ( 17 ), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half‐life. This compound represents a promising lead that warrants further evaluation. 相似文献
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The Discovery of Potent Nonstructural Protein 5A (NS5A) Inhibitors with a Unique Resistance Profile—Part 2 下载免费PDF全文
Florian Wakenhut Thien Duc Tran Dr. Chris Pickford Stephen Shaw Dr. Mike Westby Caroline Smith‐Burchnell Lesa Watson Michael Paradowski Dr. Jared Milbank David Stonehouse Dr. Kathy Cheung Dr. Robert Wybrow Dr. Felice Daverio Dr. Samuel Crook Keith Statham Dr. David Leese Dr. Darren Stead Fiona Adam Duncan Hay Dr. Lee R. Roberts Jean‐Yves Chiva Carly Nichols Dr. David C. Blakemore Gilles H. Goetz Dr. Ye Che Iain Gardner Satish Dayal Dr. Andrew Pike Rob Webster Dr. David C. Pryde 《ChemMedChem》2014,9(7):1387-1396
In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl‐linked pyrrolidine NS5A replication complex inhibitors were probed and structure–activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H‐bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second‐generation antiviral agents targeting NS5A. 相似文献
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Jose Ignacio Martin Hernando Dr. Jesus Maria Ontoria Dr. Savina Malancona Barbara Attenni Fabrizio Fiore Fabio Bonelli Uwe Koch Dr. Stefania Di Marco Dr. Stefania Colarusso Simona Ponzi Nadia Gennari Sue Ellen Vignetti Maria del Rosario Rico Ferreira Dr. Jörg Habermann Dr. Michael Rowley Dr. Frank Narjes Dr. 《ChemMedChem》2009,4(10):1695-1713
Infections caused by the hepatitis C virus (HCV) are a significant world health problem for which novel therapies are in urgent demand. The NS5B polymerase of HCV is responsible for the replication of viral RNA and has been a prime target in the search for novel treatment options. We had discovered allosteric finger‐loop inhibitors based on a thieno[3,2‐b]pyrrole scaffold as an alternative to the related indole inhibitors. Optimization of the thienopyrrole series led to several N‐acetamides with submicromolar potency in the cell‐based replicon assay, but they lacked oral bioavailability in rats. By linking the N4‐position to the ortho‐position of the C5‐aryl group, we were able to identify the tetracyclic thienopyrrole 40 , which displayed a favorable pharmacokinetic profile in rats and dogs and is equipotent with recently disclosed finger‐loop inhibitors based on an indole scaffold. 相似文献
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Anti‐Dengue‐Virus Activity and Structure–Activity Relationship Studies of Lycorine Derivatives 下载免费PDF全文
Peng Wang Lin‐Feng Li Dr. Qing‐Yin Wang Dr. Lu‐Qing Shang Dr. Pei‐Yong Shi Prof. Dr. Zheng Yin 《ChemMedChem》2014,9(7):1522-1533
Dengue is a systemic viral infection that is transmitted to humans by Aedes mosquitoes. No vaccines or specific therapeutics are currently available for dengue. Lycorine, which is a natural plant alkaloid, has been shown to possess antiviral activities against flaviviruses. In this study, a series of novel lycorine derivatives were synthesized and assayed for their inhibition of dengue virus (DENV) in cell cultures. Among the lycorine analogues, 1‐acetyllycorine exhibited the most potent anti‐DENV activity (EC50=0.4 μM ) with a reduced cytotoxicity (CC50>300 μM ), which resulted in a selectivity index (CC50/EC50) of more than 750. The ketones 1‐acetyl‐2‐oxolycorine (EC50=1.8 μM ) and 2‐oxolycorine (EC50=0.5 μM ) also exhibited excellent antiviral activities with low cytotoxicity. Structure–activity relationships for the lycorine derivatives against DENV are discussed. A three‐dimensional quantitative structure–activity relationship model was established by using a comparative molecular‐field analysis protocol in order to rationalize the experimental results. Further modifications of the hydroxy group at the C1 position with retention of a ketone at the C2 position could potentially lead to inhibitors with improved overall properties. 相似文献
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Deore RR Chen GS Chang PT Chern TR Lai SY Chuang MH Lin JH Kung FL Chen CS Chiou CT Chern JW 《ChemMedChem》2012,7(5):850-860
The metal ion chelating β-N-hydroxy-γ-ketocarboxamide pharmacophore was integrated into a quinazolinone scaffold, leading to N-arylalkyl-3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives as hepatitis C virus (HCV) NS5B polymerase inhibitors. Lead optimization led to the identification of N-phenylpropyl carboxamide 9 k (IC(50) =8.8 μM). Compound 9 k possesses selectivity toward HCV1b replicon Ava.5 cells (EC(50) =17.5 μM) over parent Huh-7 cells (CC(50) =187.5 μM). Compound 9 k effects a mixed mode of NS5B inhibition, with NTP-competitive displacement properties. The interaction between 9 k and NS5B is stabilized by the presence of magnesium ions. Docking studies showed that the binding orientation of 9 k occupies the central portions of both magnesium-mediated and NTP-ribose-response binding sites within the active site region of NS5B. As a result, 3-hydroxy-4-oxo-3,4-dihydroquinazolin-2-carboxamide derivatives are disclosed herein as novel, mainly active site inhibitors of HCV NS5B polymerase. 相似文献
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Dr. Holger Siebeneicher Dr. Arwed Cleve Dr. Hartmut Rehwinkel Dr. Roland Neuhaus Dr. Iring Heisler Dr. Thomas Müller Dr. Marcus Bauser Dr. Bernd Buchmann 《ChemMedChem》2016,11(20):2261-2271
Despite the long‐known fact that the facilitative glucose transporter GLUT1 is one of the key players safeguarding the increase in glucose consumption of many tumor entities even under conditions of normal oxygen supply (known as the Warburg effect), only few endeavors have been undertaken to find a GLUT1‐selective small‐molecule inhibitor. Because other transporters of the GLUT1 family are involved in crucial processes, these transporters should not be addressed by such an inhibitor. A high‐throughput screen against a library of ~3 million compounds was performed to find a small molecule with this challenging potency and selectivity profile. The N‐(1H‐pyrazol‐4‐yl)quinoline‐4‐carboxamides were identified as an excellent starting point for further compound optimization. After extensive structure–activity relationship explorations, single‐digit nanomolar inhibitors with a selectivity factor of >100 against GLUT2, GLUT3, and GLUT4 were obtained. The most promising compound, BAY‐876 [N4‐[1‐(4‐cyanobenzyl)‐5‐methyl‐3‐(trifluoromethyl)‐1H‐pyrazol‐4‐yl]‐7‐fluoroquinoline‐2,4‐dicarboxamide], showed good metabolic stability in vitro and high oral bioavailability in vivo. 相似文献
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Mei‐Jung Lai Ching‐Chuan Kuo Dr. Teng‐Kuang Yeh Dr. Hsing‐Pang Hsieh Dr. Li‐Tzong Chen Dr. Wen‐Yu Pan Kuang‐Yang Hsu Dr. Jang‐Yang Chang Dr. Jing‐Ping Liou Dr. 《ChemMedChem》2009,4(4):588-593
Combretastatin A‐4 derivatives : A series of combretastatin A‐4‐derived 1‐benzyl‐4,5,6‐trimethoxyindoles was designed and prepared as a novel class of potent antimitotic agents acting through the colchicine binding site on the microtubule.
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Dr. Agnieszka Gunia‐Krzyżak Katarzyna Pańczyk Dr. Anna M. Waszkielewicz Prof. Henryk Marona 《ChemMedChem》2015,10(8):1302-1325
The cinnamamide scaffold has been incorporated in to the structure of numerous organic compounds with therapeutic potential. The scaffold enables multiple interactions, such as hydrophobic, dipolar, and hydrogen bonding, with important molecular targets. Additionally, the scaffold has multiple substitution options providing the opportunity to optimize and modify the pharmacological activity of the derivatives. In particular, cinnamamide derivatives have exhibited therapeutic potential in animal models of both central and peripheral nervous system disorders. Some have undergone clinical trials and were introduced on to the pharmaceutical market. The diverse activities observed in the nervous system included anticonvulsant, antidepressant, neuroprotective, analgesic, anti‐inflammatory, muscle relaxant, and sedative properties. Over the last decade, research has focused on the molecular mechanisms of action of these derivatives, and the data reported in the literature include targeting the γ‐aminobutyric acid type A (GABAA) receptors, N‐methyl‐D ‐aspartate (NMDA) receptors, transient receptor potential (TRP) cation channels, voltage‐gated potassium channels, histone deacetylases (HDACs), prostanoid receptors, opioid receptors, and histamine H3 receptors. Here, the literature data from reports evaluating cinnamic acid amide derivatives for activity in target‐based or phenotypic assays, both in vivo and in vitro, relevant to disorders of the central and peripheral nervous systems are analyzed and structure–activity relationships discussed. 相似文献
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Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates 下载免费PDF全文
Dr. Francine S. Katz Dr. Stevan Pecic Dr. Timothy H. Tran Dr. Ilya Trakht Laura Schneider Dr. Zhengxiang Zhu Dr. Long Ton‐That Dr. Michal Luzac Viktor Zlatanic Shivani Damera Dr. Joanne Macdonald Prof. Dr. Donald W. Landry Prof. Dr. Liang Tong Prof. Dr. Milan N. Stojanovic 《Chembiochem : a European journal of chemical biology》2015,16(15):2205-2215
Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups—Mannich phenols and general bases—that are capable of reactivating OPC‐inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE. 相似文献
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Structure–Activity Relationships of JMV4463, a Vectorized Cathepsin D Inhibitor with Antiproliferative Properties: The Unique Role of the AMPA‐Based Vector 下载免费PDF全文
Dr. Lubomir L. Vezenkov Clément A. Sanchez Dr. Virginie Bellet Dr. Vincent Martin Dr. Marie Maynadier Dr. Nadir Bettache Prof. Vincent Lisowski Prof. Jean Martinez Dr. Marcel Garcia Dr. Muriel Amblard Dr. Jean‐François Hernandez 《ChemMedChem》2016,11(3):302-308
Cathepsin D (CathD) is overexpressed and secreted by several solid tumors and stimulates their growth, the mechanism of which is still not understood. In this context, the pepstatin bioconjugate JMV4463 [Ac‐arg‐O2Oc‐(Val)3‐Sta‐Ala‐Sta‐(AMPA)4‐NH2; O2Oc=8‐amino‐3,6‐dioxaoctanoyl, Sta=statine, AMPA=ortho‐aminomethylphenylacetyl], containing a new kind of cell‐penetrating vector, was previously shown to exhibit potent antiproliferative effects in vitro and to delay the onset of tumors in vivo. In this study, we performed a structure–activity relationship analysis to evaluate the significance of the inhibitor and vector moieties of JMV4463. By modifying both statine residues of pepstatin we found that the antiproliferative activity is correlated with CathD inhibition, supporting a major role of the catalytic activity of intracellular CathD in cancer cell proliferation. Replacing the vector composed of four AMPA units with other vectors was found to abolish cytotoxicity, although all of the conjugates enabled pepstatin transport into cells. In addition, the AMPA4 vector must be localized at the C terminus of the bioconjugate. The unexpected importance of the vector structure and position for cytotoxic action suggests that AMPA4 enables pepstatin to inhibit the proteolysis of critical CathD substrates involved in cell proliferation via a unique mechanism of action. 相似文献
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Cover Picture: Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates (ChemBioChem 15/2015) 下载免费PDF全文
Dr. Francine S. Katz Dr. Stevan Pecic Dr. Timothy H. Tran Dr. Ilya Trakht Laura Schneider Dr. Zhengxiang Zhu Dr. Long Ton‐That Dr. Michal Luzac Viktor Zlatanic Shivani Damera Dr. Joanne Macdonald Prof. Dr. Donald W. Landry Prof. Dr. Liang Tong Prof. Dr. Milan N. Stojanovic 《Chembiochem : a European journal of chemical biology》2015,16(15):2113-2113
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Mark J. Thompson Dr. Jennifer C. Louth Gemma K. Greenwood Dr. Fiona J. Sorrell Sandra G. Knight Nathan B. P. Adams Beining Chen Dr. 《ChemMedChem》2010,5(9):1476-1488
Amide derivatives of 2,4‐diarylthiazole‐5‐carboxylic acids were synthesised and tested for efficacy in a cell line model of prion disease. A number of compounds demonstrating antiprion activity were thereby identified from the screening libraries, showing improved potency and reproducibility of results relative to amide derivatives of the related 2,4‐diphenyl‐5‐aminothiazole, which have been documented previously. Thus, 'switching' the sense of the amide bond at thiazole C5 revealed a more promising lead series of potential prion disease therapeutics. Furthermore, 3,5‐diaryl‐1,2,4‐thiadiazoles isolated as by‐products during library synthesis provided a handful of additional examples possessing an antiprion effect, thereby augmenting the set of newly identified active compounds. Evaluation of binding to cellular prion protein (PrPC) showed only weak affinities at best, suggesting that the newly identified antiprion agents do not mediate their biological effect through direct interaction with PrPC. 相似文献
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Isao Miyazaki Siro Simizu Dr. Keisuke Ishida Dr. Hiroyuki Osada Prof. 《Chembiochem : a European journal of chemical biology》2009,10(5):838-843
Covalent bonds not required : We describe a novel approach in which the concepts of fragment‐based ligand discovery are combined with chemical array techniques to yield bivalent inhibitors. A pair of fragments is mixed and covalently attached to a glass slide by photolinking immobilization. The method does not require the compounds to have specific functional groups, and tedious steps for protein purification are avoided. Thus, the on‐chip fragment‐based approach is relatively simple and efficient for obtaining high‐affinity ligands.
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Dr. Stefan Peukert Dr. Feng He Miao Dai Rui Zhang Yingchuan Sun Dr. Karen Miller‐Moslin Michael McEwan Dr. Bharat Lagu Kate Wang Dr. Naeem Yusuff Aaron Bourret Arun Ramamurthy Dr. Wieslawa Maniara Adam Amaral Anthony Vattay Anlai Wang Ribo Guo Jing Yuan John Green Dr. Juliet Williams Dr. Silvia Buonamici Dr. Joseph F. Kelleher III Dr. Marion Dorsch 《ChemMedChem》2013,8(8):1261-1265