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https://www.readbyqxmd.com/read/28433778/novel-lipid-mimetic-prodrugs-delivering-active-compounds-to-adipose-tissue
#1
Andrea Mattarei, Andrea Rossa, Veronica Bombardelli, Michele Azzolini, Martina La Spina, Cristina Paradisi, Mario Zoratti, Lucia Biasutto
Obesity and associated pathologies are a dramatically growing problem. New therapies to prevent and/or cure them are strongly needed. Adipose tissue is a logical target for pharmacological intervention, since it is now recognized to exert an important endocrine function, secreting a variety of adipokines affecting, for example, adiposity and insulin resistance. This proof of principle work focuses on the development of novel lipid-mimetic prodrugs reaching fat deposits by the same lymphatic absorption route followed by dietary triglycerides...
April 13, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28433708/toxicological-characterisation-of-two-novel-selective-aryl-hydrocarbon-receptor-modulators-in-sprague-dawley-rats
#2
Selma Mahiout, Jere Lindén, Javier Esteban, Ismael Sánchez-Pérez, Satu Sankari, Lars Pettersson, Helen Håkansson, Raimo Pohjanvirta
The aryl hydrocarbon receptor (AHR) mediates the toxicity of dioxins, but also plays important physiological roles. Selective AHR modulators, which elicit some effects imparted by this receptor without causing the marked toxicity of dioxins, are presently under intense scrutiny. Two novel such compounds are IMA-08401 (N-acetyl-N-phenyl-4-acetoxy-5-chloro-1,2-dihydro-1-methyl-2-oxo-quinoline-3-carboxamide) and IMA-07101 (N-acetyl-N-(4-trifluoromethylphenyl)-4-acetoxy-1,2-dihydro-5-methoxy-1-methyl-2-oxo-quinoline-3-carboxamide)...
April 19, 2017: Toxicology and Applied Pharmacology
https://www.readbyqxmd.com/read/28430430/design-synthesis-and-evaluation-of-novel-2-6-disubstituted-phenol-derivatives-as-general-anesthetics
#3
Linlin Qin, Lei Ren, Songlin Wan, Guoliang Liu, Xinfeng Luo, Zhenhong Liu, Fangqiong Li, Yan Yu, Jianyu Liu, Yonggang Wei
A novel series of optically active 2,6-disubstituted alkylphenols with improved anesthetic profiles compared to widely used propofol were synthesized. The incorporation of the cyclopropyl group not only increased the steric effect but also introduced stereoselective effects over their anesthetic properties. Compounds 1, 2 and 6 were selected as potential candidates for further pre-clinical development including studies of their water-soluble prodrugs. Clinical studies of candidate compound 6 (Haisco HSK3486) as a general anesthetic are performed in Australia and China...
April 21, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28428091/characterization-of-the-effects-of-l-4-chlorokynurenine-on-nociception-in-rodents
#4
Tony L Yaksh, Robert Schwarcz, H Ralph Snodgrass
Upon systemic administration in rats, the prodrug L-4-chlorokynurenine (4-Cl-KYN) (AV-101) is rapidly absorbed, actively transported across the blood-brain barrier, and converted in astrocytes to 7-chlorokynurenic acid (7-Cl-KYNA), a potent and specific antagonist of the GlyB co-agonist site of the NMDA receptor. We examined the effects of 4-Cl-KYN in several rat models of hyperalgesia and allodynia and determined the concentrations of 4-Cl-KYN and newly produced 7-Cl-KYNA in serum, brain and spinal cord. Adult male rats were given 4-Cl-KYN (56, 167, 500 mg/kg), the NMDA receptor antagonist MK-801 (0...
April 17, 2017: Journal of Pain: Official Journal of the American Pain Society
https://www.readbyqxmd.com/read/28427111/-in-vitro-activity-of-mecillinam-against-urine-isolates-of-escherichia-coli-from-outpatient-departments-in-germany
#5
Michael Kresken, Barbara Körber-Irrgang, Kurt G Naber
National and international guidelines recommend fosfomycin trometamol, nitrofurantoin, nitroxoline, and pivmecillinam as first-line agents for the treatment of acute uncomplicated cystitis. Escherichia coli is by far the leading cause of community-acquired urinary tract infections. Pivmecillinam (X-SYSTO(®)) is an oral prodrug of mecillinam, a penicillin derivative that was reintroduced to the German market in March 2016. This study aimed to investigate the proportion of mecillinam-resistant strains among E...
April 20, 2017: Aktuelle Urologie
https://www.readbyqxmd.com/read/28425643/chemical-activation-in-blood-serum-and-human-cell-culture-improved-ruthenium-complex-for-catalytic-uncaging-of-alloc-protected-amines
#6
Timo Völker, Eric Meggers
Chemical as opposed to light-induced activation of caged molecules is a rapidly advancing approach to trigger biological processes. We recently introduced a ruthenium-catalyzed release of alloc-protected amines in human cells (Angew. Chem. Int. Ed. 2006, 45, 5645 and 2014, 53, 10536). A restriction of this and all other methods reported to date is a limited lifetime of the catalyst which hampers meaningful applications. In this study we address this problem with the development of a new generation of ruthenium complexes for the uncaging of alloc-protected amines with superior catalytic activity...
April 20, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28423594/the-hypoxia-activated-prodrug-evofosfamide-in-combination-with-multiple-regimens-of-radiotherapy
#7
Katarzyna J Nytko, Ivo Grgic, Sabine Bender, Janosch Ott, Matthias Guckenberger, Oliver Riesterer, Martin Pruschy
The promising treatment combination of ionizing radiation (IR) with a hypoxia-activated prodrug (HAP) is based on biological cooperation. Here we investigated the hypoxia-activated prodrug evofosfamide in combination with different treatment regimens of IR against lung A549- and head&neck UT-SCC-14-derived tumor xenografts. DNA damage-related endpoints and clonogenic cell survival of A549 and UT-SCC-14 carcinoma cells were probed under normoxia and hypoxia.Evofosfamide (TH-302) induced DNA-damage and a dose-dependent antiproliferative response in A549 cells on cellular pretreatment under hypoxia, and supra-additively reduced clonogenic survival in combination with IR...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28423064/biochemical-evaluation-of-the-anticancer-potential-of-the-polyamine-based-nanocarrier-nano11047
#8
Tracy Murray-Stewart, Elena Ferrari, Ying Xie, Fei Yu, Laurence J Marton, David Oupicky, Robert A Casero
Synthesizing polycationic polymers directly from existing drugs overcomes the drug-loading limitations often associated with pharmacologically inert nanocarriers. We recently described nanocarriers formed from a first-generation polyamine analogue, bis(ethyl)norspermine (BENSpm), that could simultaneously target polyamine metabolism while delivering therapeutic nucleic acids. In the current study, we describe the synthesis and evaluation of self-immolative nanocarriers derived from the second-generation polyamine analogue PG-11047...
2017: PloS One
https://www.readbyqxmd.com/read/28422492/a-concise-efficient-and-scalable-total-synthesis-of-thapsigargin-and-nortrilobolide-from-r-carvone
#9
Dezhi Chen, P Andrew Evans
A concise, efficient and scalable synthesis of thapsigargin and nortrilobolide from commercially available (R)-(-)-carvone was developed. Our synthetic strategy is inspired by nature's carbon-carbon bond formation sequence, which facilitates the construction of a highly functionalized sesquiterpene lactone skeleton in five steps via an enantioselective ketone alkylation and a diastereoselective pinacol cyclization. We envision that this strategy will permit the construction of other members of the family, structural analogs and provide a practical synthetic route to these important bioactive agents...
April 19, 2017: Journal of the American Chemical Society
https://www.readbyqxmd.com/read/28418664/selective-ikur-inhibitors-for-the-potential-treatment-of-atrial-fibrillation-optimization-of-the-phenyl-quinazoline-series-leading-to-clinical-candidate-5-5-phenyl-4-pyridin-2-ylmethylamino-quinazolin-2-yl-pyridine-3-sulfonamide
#10
Prashantha Gunaga, John L Lloyd, Somanadham Mummadi, Abhisek Banerjee, Naveen Kumar Dhondi, James K Hennan, Veena Subray, Ramya Jayaram, Nagendra Rajugowda, Umamaheshwar Reddy, Duraimurugan Kumaraguru, Umasankar Mandal, Dasthagiri Beldona, Ashok Kumar Adisechan, Navnath Yadav, Jayakumar Warrier, James A Johnson, Harinath Sale, Siva Prasad Putlur, Ajay Saxena, Anjaneya Chimalakonda, Sandhya Mandlekar, Mary Lee Conder, Dezhi Xing, Arun Kumar Gupta, Anuradha Gupta, Richard A Rampulla, Arvind Mathur, Paul C Levesque, Ruth R Wexler, Heather J Finlay
We have recently disclosed 5-phenyl-N-(pyridin-2-ylmethyl)-2-(pyrimidin-5-yl)quinazolin-4-amine 1 as a potent IKur current blocker with selectivity versus hERG, Na and Ca channels and an acceptable preclinical PK profile. On further characterization in vivo, Compound 1 demonstrated an unacceptable level of brain penetration. In an effort to reduce the level of brain penetration while maintaining the overall profile, SAR was developed at the C2' position for a series of close analogs by employing hydrogen bond donors...
April 18, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28417439/clinical-pharmacokinetics-of-sacubitril-valsartan-lcz696-a-novel-angiotensin-receptor-neprilysin-inhibitor
#11
REVIEW
Surya Ayalasomayajula, Thomas Langenickel, Parasar Pal, Sreedevi Boggarapu, Gangadhar Sunkara
Sacubitril/valsartan (LCZ696) is indicated for the treatment of heart failure with reduced ejection fraction. Absorption of sacubitril/valsartan and conversion of sacubitril (prodrug) to sacubitrilat (neprilysin inhibitor) was rapid with maximum plasma concentrations of sacubitril, sacubitrilat, and valsartan (angiotensin receptor blocker) reaching within 0.5, 1.5-2.0, and 2.0-3.0 h, respectively. With a two-fold increase in dose, an increase in the area under the plasma concentration-time curve was proportional for sacubitril, ~1...
April 17, 2017: Clinical Pharmacokinetics
https://www.readbyqxmd.com/read/28416547/simulating-intestinal-transporter-and-enzyme-activity-in-a-physiologically-based-pharmacokinetic-model-for-tenofovir-disoproxil-fumarate
#12
Darren M Moss, P Domanico, M Watkins, S Park, R Randolph, S Wring, J Hobson, S Rannard, M Siccardi, A Owen
Tenofovir disoproxil fumarate (TDF), a prodrug of tenofovir, has oral bioavailability (25%) limited by intestinal transport (p-glycoprotein), and intestinal degradation (carboxylesterase).….
April 17, 2017: Antimicrobial Agents and Chemotherapy
https://www.readbyqxmd.com/read/28416362/in-situ-targeted-activation-of-an-anticancer-agent-using-ultrasound-triggered-release-of-composite-droplets
#13
Marine Bezagu, Jonathan Clarhaut, Brigitte Renoux, Fabrice Monti, Mickael Tanter, Patrick Tabeling, Janine Cossy, Olivier Couture, Sebastien Papot, Stellios Arseniyadis
The efficiency of a drug is usually highly dependent on the way it is administered or delivered. As such, targeted-therapy, which requires conceiving drug-delivery vehicles that will change their state from a relatively stable structure with a very slow leak-rate to an unstable structure with a fast release, clearly improves the pharmacokinetics, the absorption, the distribution, the metabolism and the therapeutic index of a given drug. In this context, we have developed a particularly effective double stimuli-responsive drug-delivery method allowing an ultrasound-induced release of a monomethylauristatin E-glucuronide prodrug and its subsequent activation by a β-glucuronidase...
March 28, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28414916/quercetin-remodels-the-tumor-microenvironment-to-improve-the-permeation-retention-and-antitumor-effects-of-nanoparticles
#14
Kaili Hu, Lei Miao, Tyler J Goodwin, Jun Li, Qi Liu, Leaf Huang
Our previous work demonstrated that Wnt16 expression in cisplatin-damaged tumor-associated fibroblasts is a key factor contributing to cisplatin resistance in malignancies. Natural antifibrotic compounds with low toxicities are promising candidates to downregulate Wnt16 expression, improving the antitumor effect of cisplatin nanoparticles. Upon screening several natural chemicals, we found that a dietary flavonoid, quercetin, significantly suppresses Wnt16 expression in activated fibroblasts. To facilitate drug delivery, we have prepared a targeted lipid/calcium/phosphate nanoparticle formulation consisting of a prodrug of quercetin, i...
April 21, 2017: ACS Nano
https://www.readbyqxmd.com/read/28414134/targeted-intracorneal-delivery-biodistribution-of-triamcinolone-acetonide-following-topical-iontophoresis-of-cationic-amino-acid-ester-prodrugs
#15
Verena Santer, Sergio Del Río Sancho, Maria Lapteva, Yogeshvar N Kalia
The aim was to investigate intracorneal iontophoresis of biolabile triamcinolone acetonide (TA) amino acid ester prodrugs (TA-AA). Arginine and lysine esters of TA (TA-Arg and TA-Lys, respectively) were synthesized and characterized; quantification was performed by HPLC-UV and UHPLC-MS/MS. The aqueous solubility of the prodrugs (at pH 5.5) was ∼1000-fold greater than TA. Anodal iontophoresis (10min at 3mA/cm(2)) of TA-AA was investigated using isolated porcine cornea. Although no statistically significant difference was observed in total intracorneal delivery of TA (468...
April 14, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28413268/novel-propofol-derivatives-and-implications-for-anesthesia-practice
#16
REVIEW
Aiden Y Feng, Alan D Kaye, Rachel J Kaye, Kumar Belani, Richard D Urman
Propofol (2,6-diisopropylphenol) is the most commonly used intravenous agent for induction of anesthesia. It is also used for maintenance of anesthesia and sedation in both Intensive Care Units and outpatient procedural settings. Its success in the clinical setting has been a result of its rapid onset, short duration of action, and minimal side effects despite disadvantages associated with its oil emulsion formulation. Early attempts to alter the standard emulsion or to develop new formulations with cyclodextrins and micelles to resolve issues with pain upon injection, the need for antimicrobial agents, and possible hyperlipidemia have mostly failed...
January 2017: Journal of Anaesthesiology, Clinical Pharmacology
https://www.readbyqxmd.com/read/28412448/self-assembled-liposomes-of-dual-paclitaxel-phospholipid-prodrug-for-anticancer-therapy
#17
Longbing Ling, Yawei Du, Muhammad Ismail, Ruiyu He, Yongpeng Hou, Zhenglin Fu, Ying Zhang, Chen Yao, Xinsong Li
In this report, a newly liposomal formulation of paclitaxel (PTX) based on dual paclitaxel succinate glycerophosphorylcholine (Di-PTX-GPC) prodrug was developed. The Di-PTX-GPC prodrug was synthesised by conjugating PTX with GPC through esterification under N,N'-carbonyldiimidazole (CDI) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) catalytic system. Di-PTX-GPC liposomes were prepared by thin film method and characterized by dynamic light scattering (DLS) and transmission electron microscope (TEM). The results indicated that the liposomes have an average diameter of 157...
April 12, 2017: International Journal of Pharmaceutics
https://www.readbyqxmd.com/read/28412325/designing-metal-contained-enzyme-mimics-for-prodrug-activation
#18
REVIEW
Baoji Du, Dan Li, Jin Wang, Erkang Wang
Enzyme-activated prodrug therapy (EAPT) is a widely-used and effective treatment method for cancer by converting the prodrugs into the drugs at the demanded time and space, whose key step is prodrug activation. Traditional prodrug activations are mostly dependent on the natural enzymes, which are unstable, expensive and hard to be functionalized. The emerging enzyme mimics, especially the metal-contained enzyme mimics (MEMs), provide a potential chance for improving the traditional EAPT because of their high stability, low cost and easiness of preparation and functionalization...
April 12, 2017: Advanced Drug Delivery Reviews
https://www.readbyqxmd.com/read/28412183/structure-activity-relationship-analysis-of-mitochondrial-toxicity-caused-by-antiviral-ribonucleoside-analogs
#19
Zhinan Jin, April Kinkade, Ishani Behera, Shuvam Chaudhuri, Kathryn Tucker, Natalia Dyatkina, Vivek K Rajwanshi, Guangyi Wang, Andreas Jekle, David B Smith, Leo Beigelman, Julian A Symons, Jerome Deval
Recent cases of severe toxicity during clinical trials have been associated with antiviral ribonucleoside analogs (e.g. INX-08189 and balapiravir). Some have hypothesized that the active metabolites of toxic ribonucleoside analogs, the triphosphate forms, inadvertently target human mitochondrial RNA polymerase (POLRMT), thus inhibiting mitochondrial RNA transcription and protein synthesis. Others have proposed that the prodrug moiety released from the ribonucleoside analogs might instead cause toxicity. Here, we report the mitochondrial effects of several clinically relevant and structurally diverse ribonucleoside analogs including NITD-008, T-705 (favipiravir), R1479 (parent nucleoside of balapiravir), PSI-7851 (sofosbuvir), and INX-08189 (BMS-986094)...
April 12, 2017: Antiviral Research
https://www.readbyqxmd.com/read/28408201/spatio-temporal-control-strategy-of-drug-delivery-systems-based-nano-structures
#20
REVIEW
Nahla Rahoui, Bo Jiang, Nadia Taloub, Yu Dong Huang
The drug instability, toxicity and the barrier to the target area necessitate a suitable drug delivery system with an external or internal control of the release. Spatio-temporal control using a surface functionalized nano-carrier seems to be the best alternative for guided drug delivery and release. This manuscript provides a broad spectrum about the drug carrier interface modification to cover the need for temporal drug delivery control under neglect side effects. On the other hand, recent advances related to the drug vehicle are highlighted, besides physical (Electric field, magnetic field, light) or mechanical (Ultrasound, mechanical strain), chemical (pH, redox gradient, enzyme) stimuli mediated DDS...
April 10, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
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