Chris Bevan

Bio: Chris Bevan is an academic researcher from GlaxoSmithKline. The author has contributed to research in topics: Solvation & Partition coefficient. The author has an hindex of 12, co-authored 12 publications receiving 1404 citations. Previous affiliations of Chris Bevan include University College London & The Hertz Corporation.

Chromatographic Hydrophobicity Index by Fast-Gradient RP-HPLC: A High-Throughput Alternative to log P/log D.

Abstract: A new chromatographic hydrophobicity index (CHI) is described which can be used as part of a protocol for high-throughput (50−100 compounds/day) physicochemical property profiling for rational drug design. The index is derived from retention times (tR) observed in a fast gradient reversed-phase HPLC method. The isocratic retention factors (log k‘) were measured for a series of 76 structurally unrelated compounds by using various concentrations of acetonitrile in the mobile phase. By plotting the log k‘ as a function of the acetonitrile concentration, the slope (S) and the intercept (log k‘w) values were calculated. The previously validated index of hydrophobicity φ0 was calculated as −log k‘w/S. A good linear correlation was obtained between the gradient retention time values, tR and the isocratically determined φ0 values for the 76 compounds. The constants of this linear correlation can be used to calculate CHI. For most compounds, CHI is between 0 and 100 and in this range it approximates to the percent...

Rapid Method for the Estimation of Octanol / Water Partition Coefficient (Log Poct) from Gradient RP-HPLC Retention and a Hydrogen Bond Acidity Term (Sigma alpha2H)

Abstract: We propose a rapid method for the measurement of octanol/water partition coefficients (log P(oct)) via fast gradient reversed phase retention and the calculation of the hydrogen bond acidity of the compounds. The cycle time of the generic gradient HPLC method is 5 minutes. The general solvation equation obtained for the log Poct values and the fast gradient Chromatographic Hydrophobicity Indices with acetonitrile (CHI(ACN)) and methanol

Rapid Gradient RP-HPLC Method for Lipophilicity Determination: A Solvation Equation Based Comparison with Isocratic Methods

Abstract: The chromatographic hydrophobicity index (CHI) obtained from high-throughput gradient elution reversed-phase HPLC with ODS column and acetonitrile mobile phase has been shown to be well correlated with log k values obtained by isocratic elution in the same system; between CHI and log k50, the correlation coefficient was 0.99 for a very diverse set of 55 compounds. CHI and log k50 are moderately correlated with log P (water/octanol), and both can be used as alternative measures of lipophilicity. Analyses using the general solvation equation of Abraham shows that the solute factors that influence CHI and log k50 are not entirely the same as those that influence log P, so that neither CHI nor log k50 can be used as a direct measure of log P and vice versa. However, the factors that influence CHI are qualitatively and quantitatively the same as those that influence log k50, so that the rapidly determined CHI indexes encode exactly the same information as do isocratic log k values.

Drug-Like Properties: Concepts, Structure Design and Methods from ADME to Toxicity Optimization

Abstract: Of the thousands of novel compounds that a drug discovery project team invents and that bind to the therapeutic target, typically only a fraction of these have sufficient ADME/Tox properties to become a drug product. Understanding ADME/Tox is critical for all drug researchers, owing to its increasing importance in advancing high quality candidates to clinical studies and the processes of drug discovery. If the properties are weak, the candidate will have a high risk of failure or be less desirable as a drug product. This book is a tool and resource for scientists engaged in, or preparing for, the selection and optimization process. The authors describe how properties affect in vivo pharmacological activity and impact in vitro assays. Individual drug-like properties are discussed from a practical point of view, such as solubility, permeability and metabolic stability, with regard to fundamental understanding, applications of property data in drug discovery and examples of structural modifications that have achieved improved property performance. The authors also review various methods for the screening (high throughput), diagnosis (medium throughput) and in-depth (low throughput) analysis of drug properties. * Serves as an essential working handbook aimed at scientists and students in medicinal chemistry * Provides practical, step-by-step guidance on property fundamentals, effects, structure-property relationships, and structure modification strategies * Discusses improvements in pharmacokinetics from a practical chemist's standpoint

Generation of a set of simple, interpretable ADMET rules of thumb.

Abstract: A set of simple, consistent structure-property guides have been determined from an analysis of a number of key ADMET assays run within GSK: solubility, permeability, bioavailability, volume of distribution, plasma protein binding, CNS penetration, brain tissue binding, P-gp efflux, hERG inhibition, and cytochrome P450 1A2/2C9/2C19/2D6/3A4 inhibition. The rules have been formulated using molecular properties that chemists intuitively know how to alter in a molecule, namely, molecular weight, logP, and ionization state. The rules supplement the more predictive black-box models available to us by clearly illustrating the key underlying trends, which are in line with reports in the literature. It is clear from the analyses reported herein that almost all ADMET parameters deteriorate with either increasing molecular weight, logP, or both, with ionization state playing either a beneficial or detrimental affect depending on the parameter in question. This study re-emphasizes the need to focus on a lower molecular weight and logP area of physicochemical property space to obtain improved ADMET parameters.

Lipophilicity in drug discovery.

Abstract: Importance of the field: The role of lipophilicity in determining the overall quality of candidate drug molecules is of paramount importance. Recent developments suggest that, as well as determinin...