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ACS Medicinal Chemistry Letters

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https://www.readbyqxmd.com/read/28217261/affinity-of-rimantadine-enantiomers-against-influenza-a-m2-protein-revisited
#1
Antonios Drakopoulos, Christina Tzitzoglaki, Chulong Ma, Kathrin Freudenberger, Anja Hoffmann, Yanmei Hu, Günter Gauglitz, Michaela Schmidtke, Jun Wang, Antonios Kolocouris
Recent findings from solid state NMR (ssNMR) studies suggested that the (R)-enantiomer of rimantadine binds to the full M2 protein with higher affinity than the (S)-enantiomer. Intrigued by these findings, we applied functional assays, such as antiviral assay and electrophysiology (EP), to evaluate the binding affinity of rimantadine enantiomers to the M2 protein channel. Unexpectedly, no significant difference was found between the two enantiomers. Our experimental data based on the full M2 protein function were further supported by alchemical free energy calculations and isothermal titration calorimetry (ITC) allowing an evaluation of the binding affinity of rimantadine enantiomers to the M2TM pore...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197324/-125-i-f56-peptide-as-radioanalysis-agent-targeting-vegfr1-in-mice-xenografted-with-human-gastric-tumor
#2
Hua Zhu, Chuanke Zhao, Fei Liu, Lixin Wang, Junnan Feng, Chengchao Shou, Zhi Yang
(125)I-Radiolabeled F56 peptide was designed as a radioactive analogue of F56 (peptide WHSDMEWWYLLG) to bind with VEGFR1 receptor. It was synthesized in high radiochemical yield and specific activity. The in vitro stability of (125)I-F56 was tested, and the bioactivity of (125)I-F56 was confirmed by both cell uptake and binding affinity measurement in VEGFR1 positive BGC-823 cells. The time-radioactivity relationship and biodistribution of (125)I-F56 tracer were conducted using nude mice bearing human gastric carcinoma BGC-823, by noninvasive micro-SPECT/CT imaging...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197323/novel-2-substituted-7-azaindole-and-7-azaindazole-analogues-as-potential-antiviral-agents-for-the-treatment-of-influenza
#3
Upul K Bandarage, Michael P Clark, Emanuele Perola, Huai Gao, Marc D Jacobs, Alice Tsai, Jeffery Gillespie, Joseph M Kennedy, François Maltais, Mark W Ledeboer, Ioana Davies, Wenxin Gu, Randal A Byrn, Kwame Nti Addae, Hamilton Bennett, Joshua R Leeman, Steven M Jones, Colleen O'Brien, Christine Memmott, Youssef Bennani, Paul S Charifson
JNJ-63623872 (2) is a first-in-class, orally bioavailable compound that offers significant potential for the treatment of pandemic and seasonal influenza. Early lead optimization efforts in our 7-azaindole series focused on 1,3-diaminocyclohexyl amide and urea substitutions on the pyrimidine-7-azaindole motif. In this work, we explored two strategies to eliminate observed aldehyde oxidase (AO)-mediated metabolism at the 2-position of these 7-azaindole analogues. Substitution at the 2-position of the azaindole ring generated somewhat less potent analogues, but reduced AO-mediated metabolism...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197322/discovery-of-novel-orally-bioavailable-%C3%AE-amino-acid-azaindole-inhibitors-of-influenza-pb2
#4
Luc J Farmer, Michael P Clark, Michael J Boyd, Emanuele Perola, Steven M Jones, Alice Tsai, Marc D Jacobs, Upul K Bandarage, Mark W Ledeboer, Tiansheng Wang, Hongbo Deng, Brian Ledford, Wenxin Gu, John P Duffy, Randy S Bethiel, Dean Shannon, Randal A Byrn, Joshua R Leeman, Rene Rijnbrand, Hamilton B Bennett, Colleen O'Brien, Christine Memmott, Kwame Nti-Addae, Youssef L Bennani, Paul S Charifson
In our efforts to develop novel small-molecule inhibitors for the treatment of influenza, we utilized molecular modeling and the X-ray crystal structure of the PB2 subunit of the influenza polymerase to optimize a series of acyclic β-amino acid inhibitors, highlighted by compound 4. Compound 4 showed good oral exposure in both rat and mouse. More importantly, it showed strong potency versus multiple influenza-A strains, including pandemic 2009 H1N1 and avian H5N1 strains and showed a strong efficacy profile in a mouse influenza model even when treatment was initiated 48 h after infection...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197321/discovery-of-novel-allosteric-hcv-ns5b-inhibitors-2-lactam-containing-thiophene-carboxylates
#5
Pan Li, Warren Dorsch, David J Lauffer, Darius Bilimoria, Nathalie Chauret, John J Court, Sanjoy Kumar Das, Francois Denis, Nagraj Mani, Suganthini Nanthakumar, Olivier Nicolas, B Govinda Rao, Steven Ronkin, Subajini Selliah, Rebecca S Shawgo, Ralph Stearns, Qing Tang, Nathan D Waal, Jeremy Green
Lomibuvir (1) is a non-nucleoside, allosteric inhibitor of the hepatitis C virus NS5B polymerase with demonstrated clinical efficacy. Further development efforts within this class of inhibitor focused on improving the antiviral activity and physicochemical and pharmacokinetic properties. Recently, we reported the development of this series, leading to compound 2, a molecule with comparable potency and an improved physicochemical profile relative to 1. Further exploration of the amino amide-derived side chain led to a series of lactam derivatives, inspired by the X-ray crystal structure of related thiophene carboxylate inhibitors...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197320/synthesis-biological-evaluation-and-autophagy-mechanism-of-12n-substituted-sophoridinamines-as-novel-anticancer-agents
#6
Chongwen Bi, Na Zhang, Peng Yang, Cheng Ye, Yanxiang Wang, Tianyun Fan, Rongguang Shao, Hongbin Deng, Danqing Song
A series of 12N-substituted sophoridinamine derivatives were synthesized and evaluated for their cytotoxic activities in human HepG2 hepatoma cells. Structure-activity relationship revealed that introduction of a suitable arylidene or arylethyl at the N'-end could greatly enhance antiproliferation potency. Among them, compound 6b possessing a N'-trimethoxyphenyl methylene exhibited potent antiproliferation effect against three human tumor cell lines including HepG2, leukemia (K562), and breast cancer (HMLE), with IC50 between 0...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197319/structure-based-design-of-non-natural-peptidic-macrocyclic-mcl-1-inhibitors
#7
Jeffrey W Johannes, Stephanie Bates, Carl Beigie, Matthew A Belmonte, John Breen, Shenggen Cao, Paolo A Centrella, Matthew A Clark, John W Cuozzo, Christoph E Dumelin, Andrew D Ferguson, Sevan Habeshian, David Hargreaves, Camil Joubran, Steven Kazmirski, Anthony D Keefe, Michelle L Lamb, Haiye Lan, Yunxia Li, Hao Ma, Scott Mlynarski, Martin J Packer, Philip B Rawlins, Daniel W Robbins, Haidong Shen, Eric A Sigel, Holly H Soutter, Nancy Su, Dawn M Troast, Haiyun Wang, Kate F Wickson, Chengyan Wu, Ying Zhang, Qiuying Zhao, Xiaolan Zheng, Alexander W Hird
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197318/discovery-of-vu0467485-az13713945-an-m4-pam-evaluated-as-a-preclinical-candidate-for-the-treatment-of-schizophrenia
#8
Michael R Wood, Meredith J Noetzel, Bruce J Melancon, Michael S Poslusney, Kellie D Nance, Miguel A Hurtado, Vincent B Luscombe, Rebecca L Weiner, Alice L Rodriguez, Atin Lamsal, Sichen Chang, Michael Bubser, Anna L Blobaum, Darren W Engers, Colleen M Niswender, Carrie K Jones, Nicholas J Brandon, Michael W Wood, Mark E Duggan, P Jeffrey Conn, Thomas M Bridges, Craig W Lindsley
Herein, we report the structure-activity relationships within a series of potent, selective, and orally bioavailable muscarinic acetylcholine receptor 4 (M4) positive allosteric modulators (PAMs). Compound 6c (VU0467485) possesses robust in vitro M4 PAM potency across species and in vivo efficacy in preclinical models of schizophrenia. Coupled with an attractive DMPK profile and suitable predicted human PK, 6c (VU0467485) was evaluated as a preclinical development candidate.
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197317/comparison-of-fluorinated-and-nonfluorinated-lipids-in-self-adjuvanting-delivery-systems-for-peptide-based-vaccines
#9
Waleed M Hussein, Saori Mukaida, Fazren Azmi, Stacey Bartlett, Celine Olivier, Michael R Batzloff, Michael F Good, Mariusz Skwarczynski, Istvan Toth
Safe immunostimulants (adjuvants) are essential for the development of highly potent peptide-based vaccines. This study examined for the first time whether fluorinated lipids could stimulate humoral immunity in vivo when conjugated to peptide antigen. The impact of fluorination on humoral immunity was tested using a library of peptide-based vaccine candidates against the group A streptococcus (GAS). The fluorinated constructs stimulated similar mouse IgG titers to those elicited by complete Freund's adjuvant (CFA) and were higher than those produced in mice that received the nonfluorinated constructs...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197316/design-and-synthesis-of-novel-selective-gpr40-agopams
#10
Christopher W Plummer, Matthew J Clements, Helen Chen, Murali Rajagopalan, Hubert Josien, William K Hagmann, Michael Miller, Maria E Trujillo, Melissa Kirkland, Daniel Kosinski, Joel Mane, Michele Pachanski, Boonlert Cheewatrakoolpong, Andrew F Nolting, Robert Orr, Melodie Christensen, Louis-Charles Campeau, Michael J Wright, Randal Bugianesi, Sarah Souza, Xiaoping Zhang, Jerry Di Salvo, Adam B Weinglass, Richard Tschirret-Guth, Ravi Nargund, Andrew D Howard, Steven L Colletti
GPR40 is a G-protein-coupled receptor expressed primarily in pancreatic islets and intestinal L-cells that has been a target of significant recent therapeutic interest for type II diabetes. Activation of GPR40 by partial agonists elicits insulin secretion only in the presence of elevated blood glucose levels, minimizing the risk of hypoglycemia. GPR40 agoPAMs have shown superior efficacy to partial agonists as assessed in a glucose tolerability test (GTT). Herein, we report the discovery and optimization of a series of potent, selective GPR40 agoPAMs...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197315/affinity-based-selectivity-profiling-of-an-in-class-selective-competitive-inhibitor-of-acyl-protein-thioesterase-2
#11
Sang Joon Won, Joseph D Eschweiler, Jaimeen D Majmudar, Fei San Chong, Sin Ye Hwang, Brandon T Ruotolo, Brent R Martin
Activity-based protein profiling (ABPP) has revolutionized the discovery and optimization of active-site ligands across distinct enzyme families, providing a robust platform for in-class selectivity profiling. Nonetheless, this approach is less straightforward for profiling reversible inhibitors and does not access proteins outside the ABPP probe's target profile. While the active-site competitive acyl protein thioesterase 2 inhibitor ML349 (Ki = 120 nM) is highly selective within the serine hydrolase enzyme family, it could still interact with other cellular targets...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197314/combretastatin-a4-%C3%AE-galactosyl-conjugates-for-ovarian-cancer-prodrug-monotherapy
#12
Tomohiro Doura, Kazuaki Takahashi, Yasumitsu Ogra, Noriyuki Suzuki
Chemotherapy for ovarian cancer often causes severe side effects. As candidates for combretastatin A4 (CA4) prodrug for ovarian cancer prodrug monotherapy (PMT), we designed and synthesized two β-galactose-conjugated CA4s (CA4-βGals), CA4-βGal-1 and CA4-βGal-2. CA4 was liberated from CA4-βGals by β-galactosidase, an enzyme more strongly expressed in ovarian cancer cells than normal cells. CA4-βGal-2, which has a self-immolative benzyl linker between CA4 and the β-galactose moiety, was more cytotoxic to ovarian cancer cell lines than CA4-βGal-1 without a linker...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197313/from-dynamic-combinatorial-chemistry-to-in-vivo-evaluation-of-reversible-and-irreversible-myeloperoxidase-inhibitors
#13
Jalal Soubhye, Michel Gelbcke, Pierre Van Antwerpen, François Dufrasne, Mokhtaria Yasmina Boufadi, Jean Nève, Paul G Furtmüller, Christian Obinger, Karim Zouaoui Boudjeltia, Franck Meyer
The implementation of dynamic combinatorial libraries allowed the determination of highly active reversible and irreversible inhibitors of myeloperoxidase (MPO) at the nanomolar level. Docking experiments highlighted the interaction between the most active ligands and MPO, and further kinetic studies defined the mode of inhibition of these compounds. Finally, in vivo evaluation showed that one dose of irreversible inhibitors is able to suppress the activity of MPO after inducing inflammation.
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197312/identification-and-mechanistic-evaluation-of-hemozoin-inhibiting-triarylimidazoles-active-against-plasmodium-falciparum
#14
Kathryn J Wicht, Jill M Combrinck, Peter J Smith, Roger Hunter, Timothy J Egan
In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against Plasmodium falciparum. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of P...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197311/synthesis-and-evaluation-of-thiazoloquinolinones-with-linkers-to-enable-targeting-of-cd38
#15
Stephen S Scully, Zachary J Minden, Ratul Mukerji, Elizaveta Andrianova, James Kaberna, Scott Lentini, Carlos Tassa, Zhaolin Wang, Susan Low, Kevin A McDonnell
Several monoclonal antibodies and inhibitors targeting CD38, an ectoenzyme overexpressed on malignant plasma cells, have previously been discovered. Herein, we expand structure-activity relationships of reported small-molecule thiazoloquinolinones and show that several 4-cyclohexylamino analogues have potent binding affinity for CD38 using surface plasmon resonance. Moreover, active amine analogues could be acylated and functionalized with alkyne and fluorescein groups. Fluorescein analogue 21 bound selectively to CD38 overexpressing cells, demonstrating the potential utility of thiazoloquinolinones as small-molecule conjugates for the delivery of therapeutic and imaging agents...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197310/novel-18-f-labeled-1-hydroxyanthraquinone-derivatives-for-necrotic-myocardium-imaging
#16
Ai-Yan Ji, Qiao-Mei Jin, Dong-Jian Zhang, Hua Zhu, Chang Su, Xing-Hua Duan, Li Bian, Zi-Ping Sun, Yi-Cheng Ni, Jian Zhang, Zhi Yang, Zhi-Qi Yin
Rapid detection and precise evaluation of myocardial viability is necessary to aid in clinical decision making whether to recommend revascularization for patients with myocardial infarction (MI). Three novel (18)F-labeled 1-hydroxyanthraquinone derivatives were synthesized, characterized, and evaluated as potential necrosis avid imaging agents for assessment of myocardial viability. Among these tracers, [(18)F]FA3OP emerged as the most promising compound with best stability and highest targetability. Clear PET images of [(18)F]FA3OP were obtained in rat model of myocardial infarction and reperfusion at 1 h after injection...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197309/structure-guided-design-of-novel-potent-and-selective-macrocyclic-plasma-kallikrein-inhibitors
#17
Zhe Li, James Partridge, Abel Silva-Garcia, Peter Rademacher, Andreas Betz, Qing Xu, Hing Sham, Yunjin Hu, Yuqing Shan, Bin Liu, Ying Zhang, Haijuan Shi, Qiong Xu, Xubo Ma, Li Zhang
A series of macrocyclic analogues were designed and synthesized based on the cocrystal structure of small molecule plasma kallikrein (pKal) inhibitor, 2, with the pKal protease domain. This led to the discovery of a potent macrocyclic pKal inhibitor 29, with an IC50 of 2 nM for one olefinic isomer and 42.3 nM for the other olefinic isomer.
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197308/novel-small-molecule-probes-for-metastatic-melanoma
#18
Anyanee Kamkaew, Nanyan Fu, Weibo Cai, Kevin Burgess
Actively targeting probe 1b, an unsymmetrical bivalent dipeptide mimic, selectively bound melanoma over healthy skin tissue in histological samples from patients and Sinclair swine. Modifications to 1b gave agents 2-4 that contain a near-IR aza-BODIPY fluor. Contrary to our expectations, symmetrical probe 3 gave the highest melanoma-to-healthy skin selectivity in histochemistry and experiments with live cells; this was surprising because 2, not 3, is unsymmetrical like the original lead 1. Optical imaging of 3 in a mouse melanoma model failed to show tumor accumulation in vivo, but the probe did selectively accumulate in the tumor (some in lung and less in the liver) as proven by analysis of the organs post mortem...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197307/synthesis-and-antitumor-activity-evaluation-of-a-novel-combi-nitrosourea-prodrug-bgcnu
#19
Yameng Wang, Ting Ren, Xinxin Lai, Guohui Sun, Lijiao Zhao, Na Zhang, Rugang Zhong
Chloroethylnitrosoureas (CENUs) are an important type of alkylating agent employed in the clinical treatment of cancer. However, the anticancer efficacy of CENUs is greatly decreased by a DNA repairing enzyme, O(6)-alkylguanine-DNA alkyltransferase (AGT), by preventing the formation of interstrand cross-links (ICLs). In this study, a combi-nitrosourea prodrug, namely, N-(2-chloroethyl)-N'-2-(O(6)-benzyl-9-guanine)ethyl-N-nitrosourea (BGCNU), which possesses an O(6)-benzylguanine (O(6)-BG) derivative and CENU pharmacophores simultaneously, was synthesized and evaluated for its ability to induce ICLs...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28197306/potent-antifungal-synergy-of-phthalazinone-and-isoquinolones-with-azoles-against-candida-albicans
#20
Aaron D Mood, Ilandari Dewage Udara Anulal Premachandra, Stanley Hiew, Fuqiang Wang, Kevin A Scott, Nathan J Oldenhuis, Haoping Liu, David L Van Vranken
Four phthalazinones (CIDs 22334057, 22333974, 22334032, 22334012) and one isoquinolone (CID 5224943) were previously shown to be potent enhancers of antifungal activity of fluconazole against Candida albicans. Several even more potent analogues of these compounds were identified, some with EC50 as low as 1 nM, against C. albicans. The compounds exhibited pharmacological synergy (FIC < 0.5) with fluconazole. The compounds were also shown to enhance the antifungal activity of isavuconazole, a recently FDA approved azole antifungal...
February 9, 2017: ACS Medicinal Chemistry Letters
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