732 results

Design, Synthesis, and Evaluation of Analogs of Initiation Factor 4E (eIF4E) Cap-binding Antagonist Bn7-GMP

Aberrant regulation of cap-dependent translation has been frequently observed in the development of cancer. Association of the cap-binding protein eIF4E with N(7)-methylated guanosine capped mRNA is the rate limiting step governing translation initiation; and therefore represents an attractive process for cancer drug discovery. Previously, replacement of the 7-Me group of the Me(7)-guanosine monophosphate with a … Continued


Design and Synthesis of 4-amino-2-phenylquinazolines as Novel Topoisomerase I Inhibitors with Molecular Modeling

4-Amino-2-phenylquinazolines 7 were designed as bioisosteres of 3-arylisoquinolinamines 6 that were energy minimized to provide stable conformers. Interestingly, the 2-phenyl ring of 4-amino-2-phenylquinazolines was parallel to the quinazoline ring and improved their DNA intercalation ability in the DNA-topo I complex.  


Prediction of Clearance of Eleven Drugs and Associated Variability in Neonates

Prediction of the exposure of neonates, infants and children to xenobiotics is likely to be more successful using physiologically based pharmacokinetic models than simplistic allometric scaling, particularly in younger children. However, such models require comprehensive information on the ontogeny of anatomical, physiological and biochemical variables; data that are not available from single sources. The Simcyp® … Continued


Hologram Quantitative Structure Activity Relationship Studies on 5-HT6 Antagonists

Predictive hologram quantitative structure activity relationship (HQSAR) models were developed for a series of arylsulfonamide compounds acting as specific 5-HT6 antagonists. A training set containing 48 compounds served to establish the model. The best HQSAR model was generated using atoms, bond, and connectivity as fragment distinction and 4-7 as fragment size showing cross-validated r2(q2) value … Continued


Understanding Volume of Distribution

One of the most misunderstood pharmacokinetic (PK) parameters is volume of distribution. First of all it has numerous abbreviations (V, Vd, Vz, Vss, V1, Vc, V2, etc.), and to make matters worse, many people incorrectly define the parameter. But, once you understand the meaning behind volume of distribution, you will have a solid grasp on … Continued


Physiologically-based Mechanistic Modeling to Predict Complex Drug–drug Interactions Involving Simultaneous Competitive and Time-dependent Enzyme Inhibition by Parent Compound and Its Metabolite in Both Liver and Gut—The Effect of Diltiazem on the Time-course of Exposure to Triazolam

The aim of this study was to predict the magnitude of metabolic drug-drug interaction (mDDI) between triazolam and diltiazem and its primary metabolite N-desmethyldiltiazem (MA).Relevant in vitro metabolic and inhibitory data were incorporated into a mechanistic physiologically based pharmacokinetic model within Simcyp (Version 9.1) to simulate the time-course of changes in active CYP3A4 content in … Continued


Placebo Response Changes Depending on the Neuropathic Pain Syndrome: Results of a Systematic Review and Meta-analysis

The purpose of this study was to compare placebo responses in neuropathic pain syndromes through systematic literature review and meta-analysis. We used randomized placebo-controlled trials assessing pain intensity or pain relief in any neuropathic pain syndrome published since 1995 with +AD4-/+AD0-5days follow-up. We measured placebo response as measured by pain intensity and responder rates (proportion reporting +AD4-/+AD0-50+ACU- pain … Continued


A Comparative Study of Quantitative Structure-activity Relationship Methods Based on Gallic Acid Derivatives

By using hologram quantitative structure-activity relationship (HQSAR) and comparative molecular field analysis (CoMFA) methods, the relationships between the structures of 49 gallic acid derivatives and their analgesic activity have been investigated to yield statistically reliable models with considerable predictive power. The best HQSAR model was generated using atoms, bond and connectivity as fragment distinction parameters … Continued


Calculating Urine PK Parameters

Pharmacokinetic analysis normally focuses on systemic exposure to a drug; however, much can be learned from urinary pharmacokinetic parameters. Urinary PK parameters tell you about how much drug was absorbed (at a minimum), and how much drug is eliminated through the kidney. Often it provides easy access to metabolites that are also eliminated in the urine. … Continued

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