Laurence Philippe

Intramolecular Ring-Opening Decomposition of Aryl Azetidines

Guoyun Bai, Thomas N. O’Connell, Michael A. Brodney, Christopher R. Butler et autres

The ring strain present in azetidines can lead to undesired stability issues. Herein, we described a series of N-substituted azetidines which undergo an acid-mediated intramolecular ring-opening decomposition via nucleophilic attack of a pendant amide group. Studies were conducted to understand the decomposition …

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Entry of therapeutics into the brain: Influence of exposed polarity calculated in silico and measured in vitro by supercritical fluid chromatography

Giacomo Russo, Francesco Barbato, Lucia Grumetto, Laurence Philippe et autres

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Physical Chemical Properties for Drug Design in Beyond Rule-of-Five Chemical Space

Marina Shalaeva, Gilles H. Goetz, Laurence Philippe

Medicinal Chemistry Reviews is an outstanding 680 page volume providing timely and critical reviews of important topics in medicinal chemistry. It is provided free of charge to MEDI members in electronic format. Members can also order a print copy, for the cost …

Relationship between Passive Permeability and Molecular Polarity Using Block Relevance Analysis

Gilles H. Goetz, Marina Shalaeva, Giulia Caron, Giuseppe Ermondi et autres

EPSA is an experimental descriptor of molecular polarity obtained from chromatographic retention in supercritical fluid chromatography (SFC) systems, previously shown by Goetz et al. to correlate with passive permeability of cyclic peptides. The present study focuses on EPSA in relation to passive …

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A Fast Chromatographic Method for Estimating Lipophilicity and Ionization in Nonpolar Membrane-Like Environment

Giulia Caron, Maura Vallaro, Giuseppe Ermondi, Gilles H. Goetz et autres

This study describes the design and implementation of a new chromatographic descriptor called log k'80 PLRP-S that provides information about the lipophilicity of drug molecules in the nonpolar environment, both in their neutral and ionized form. The log k'80 PLRP-S obtained on …

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Automated solvent system screening for the preparative countercurrent chromatography of pharmaceutical discovery compounds

James Bradow, Frank Riley, Laurence Philippe, Yan Qi et autres

A fully automated countercurrent chromatography system has been constructed to rapidly screen the commonly used heptane/ethyl acetate/methanol/water solvent system series and translate the results to preparative scale separations. The system utilizes "on-demand" preparation of the heptane/ethyl acetate/methanol/water solvent system upper and lower …

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Chromatographic resolution of atropisomers for toxicity and biotransformation studies in pharmaceutical research

Tony Q. Yan, Frank Riley, Laurence Philippe, Jennifier Davoren et autres

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Chemical and Computational Methods for the Characterization of Covalent Reactive Groups for the Prospective Design of Irreversible Inhibitors

Mark E. Flanagan, J. A. Abramite, Dennis P. Anderson, Ann Aulabaugh et autres

Interest in drugs that covalently modify their target is driven by the desire for enhanced efficacy that can result from the silencing of enzymatic activity until protein resynthesis can occur, along with the potential for increased selectivity by targeting uniquely positioned nucleophilic …

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EPSA: A Novel Supercritical Fluid Chromatography Technique Enabling the Design of Permeable Cyclic Peptides

Gilles H. Goetz, Laurence Philippe, Michael J. Shapiro

Most peptides are generally insufficiently permeable to be used as oral drugs. Designing peptides with improved permeability without reliable permeability monitoring is a challenge. We have developed a supercritical fluid chromatography technique for peptides, termed EPSA, which is shown here to enable …

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High Throughput Method for the Indirect Detection of Intramolecular Hydrogen Bonding

Gilles H. Goetz, William Farrell, Marina Shalaeva, Simone Sciabola et autres

A supercritical fluid chromatography method was developed for the detection of intramolecular hydrogen bonds in pharmaceutically relevant molecules. The identification of compounds likely to form intramolecular hydrogen bonds is an important drug design consideration given the correlation of intramolecular hydrogen bonding with …

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Integrating Intramolecular Hydrogen Bonding (IMHB) Considerations in Drug Discovery Using ΔlogP As a Tool

Marina Shalaeva, Giulia Caron, Yuriy A. Abramov, Thomas N. O’Connell et autres

This study demonstrates that ΔlogP(oct-tol) (difference between logP(octanol) and logP(toluene)) describes compounds propensity to form intramolecular hydrogen bonds (IMHB) and may be considered a privileged molecular descriptor for use in drug discovery and for prediction of IMHB in drug candidates. We identified …

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Biaryl-Bridged Macrocyclic Peptides: Conformational Constraint via Carbogenic Fusion of Natural Amino Acid Side Chains

Falco‐Magnus Meyer, James C. Collins, Brendan N. Borin, James Bradow et autres

A general method for constraining peptide conformations via linkage of aromatic sidechains has been developed. Macrocyclization of suitably functionalized tri-, tetra- and pentapeptides via Suzuki-Miyaura cross-coupling has been used to generate side chain to side chain, biaryl-bridged 14- to 21-membered macrocyclic peptides. …

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