Biomedical subjects

Oliver J McConnell

Publications and source records attributed to Oliver J McConnell.

6 recordsLinked to original sources

PubMed2005

Absolute configuration of C2-symmetric spiroselenurane: 3,3,3',3'-tetramethyl-1,1'-spirobi[3 H,2,1]benzoxaselenole.

The enantiomers of 3,3,3',3'-tetramethyl-1,1'-spirobi[3 H,2,1]benzoxaselenole have been separated on a chiral preparative chromatographic column. The experimental vibrational circular dichroism (VCD) spectra have been obtained for both enantiomers in CH(2)Cl(2). The theoretical VCD spectra have been obtained by means of density functional theoretical calculations with the B3 LYP density functional. From a comparison of experimental and theoretical VCD spectra, the absolute configuration of an enantiomer with positive specific rotation in CH(2)Cl(2) at 589 nm is determined to be R. This conclusion has been verified by comparing results of experimental optical rotatory dispersion (ORD) and electronic circular dichroism (ECD) to predictions of the same properties using the B3 LYP functional for the title compound.

Journal Article↗

PubMed2004

Rapid, automated screening method for enzymatic transformations using a robotic system and supercritical fluid chromatography.

An automated screening method was developed for enzymatic transformations using a robotic system and rapid chiral supercritical fluid chromatography (SFC) analysis with a run time of 1.5 min. The method accelerates the enzyme selection process for screening biocatalysts, where a large number of enzymes are evaluated for activity and enantioselectivity. Kinetic resolution of secondary alcohols by enzymatic transesterification was used as a prototype for method development. The rapid automated method can be used effectively for screening enzymes and optimizing reaction conditions in biocatalysis.

Automation↗

PubMed2004

Integrated high capacity solid phase extraction-MS/MS system for pharmaceutical profiling in drug discovery.

A method is described for use in analysis of samples from pharmaceutical profiling of early drug discovery compounds. The method consists of a high capacity autosampler which injects samples into one of two solid phase extraction columns operated in parallel for alternating trapping, washing and elution into a tandem quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) MS/MS mode. A primary method, which is useful for 80-90% of compounds, and a secondary method, which is useful for a majority of the remaining compounds, are described. No analytical HPLC column is used and the analysis rate is approximately 50 samples/h. Specificity is obtained using MRM analysis. Application of the method for high capacity analysis of metabolic stability samples is described.

Drug Design↗

PubMed2003

Determination of rat oral bioavailability of soy-derived phytoestrogens using an automated on-column extraction procedure and electrospray tandem mass spectrometry.

In recent years, consumption of herbal supplements as an alternative to pharmaceutical drug therapy has increased. For example, with the health claims labeling which describes the link between soy-protein and a reduced risk of coronary heart disease (CHD), the consumption of soy and soy-derived phytoestrogens has increased dramatically. That being said, the oral bioavailability of only a few soy phytoestrogens such as Daidzein and Genestein have been previously estimated. In this paper, we present the calculated percent of rat oral bioavailability of five soy-derived phytoestrogens (Genistein, Daidzein, Biochanin A, Coumestrol, and Zearalenone) in male Sprague-Dawley rats. The plasma quantitation required for the bioavailability calculation is performed by using a rapid on-line plasma extraction procedure for the quantitative analysis. To further speed up the analysis the rats were dosed using the 'n-in-one' (cassette) protocol. The rapid on-line extraction/quantitation methodology coupled to the cassette dosing analysis of phytoestrogens is the key point of this paper. The limit of quantitation (LOQ) for each compound was 1-1000 ng/ml with each plasma sample analysis taking less than 2 min. In general the percent oral bioavailability was determined to be between 11 and 28%.

Administration, Oral↗

PubMed2003

High throughput artificial membrane permeability assay for blood-brain barrier.

The recent advances in high throughput screening for biological activities and combinatorial chemistry have greatly expanded the number of drug candidates. Rapid screening for BBB penetration potential early in drug discovery programs provides important information for compound selection and guidance of synthesis for desirable CNS properties. In this paper, we discuss a modification of the parallel artificial membrane permeation assay (PAMPA) for the prediction of blood-brain barrier penetration (PAMPA-BBB). The assay was developed with 30 structurally diverse commercial drugs and validated with 14 Wyeth Research compounds. The PAMPA-BBB assay has the advantages of: predicting passive blood-brain barrier penetration with high success, high throughput, low cost, and reproducibility.

Animals↗

PubMed2003

Optimization of a higher throughput microsomal stability screening assay for profiling drug discovery candidates.

Metabolic stability plays an important role in the success of drug candidates. First-pass metabolism is one of the major causes of poor oral bioavailability and short half-life. Traditionally, metabolic stability was evaluated at a later stage of drug discovery and required laborious manual manipulations. With the advance of high-throughput screening, combinatorial chemistry, and early profiling of drug-like properties, automated and rapid stability assays are needed to meet the increasing demand of throughput, speed, and reproducibility at earlier stages of drug discovery. The authors describe optimization of a simple, robust, high-throughput microsomal stability assay developed in a 96-well format. The assay consists of 2 automated components: robotic sample preparation for incubation and cleanup and rapid liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) analysis to determine percent remaining of the parent compound. The reagent solutions and procedural steps were optimized for automation. Variables affecting assay results were investigated. The variability introduced by microsome preparations from different sources (various vendors and batches) was studied and indicates the need for careful control. Quality control and normalization of the stability results are critical when applying the screening data, generated at different times or research sites, to discovery projects.

Animals↗