Biomedical subjects

Larry Mallis

Publications and source records attributed to Larry Mallis.

4 recordsLinked to original sources

PubMed2006

NMR characterization of an S-linked glucuronide metabolite of the potent, novel, nonsteroidal progesterone agonist tanaproget.

Tanaproget is a first-in-class nonsteroidal progesterone receptor agonist that is being investigated for use in contraception. A major in vitro and in vivo metabolite of tanaproget formed in humans was initially characterized as a glucuronide of tanaproget. However, whether the glucuronide was linked to the nitrogen or sulfur of the benzoxazine-2-thione group in tanaproget could not be determined by liquid chromatography/mass spectrometry (LC/MS) and LC-tandem mass spectrometry analysis. To obtain additional structural details for this metabolite, additional quantities were generated from rat liver microsomal incubations and purified by high-performance liquid chromatography (HPLC) for NMR analysis. The NMR data for the metabolite confirmed that the glucuronide was covalently bound to either the sulfur or the nitrogen of the benzoxazine-2-thione moiety. The lack of key through-bond (scalar) and through-space (dipolar) one-dimensional (1D) and two-dimensional (2D) NMR couplings and correlations in the metabolite spectra (due primarily to low sample concentration) precluded an unambiguous structure elucidation. Subsequent synthesis of the S- and N-glucuronides of tanaproget from tanaproget facilitated the unambiguous regio- and stereochemical assignment of the metabolite by comparison of 1D NMR chemical shifts and scalar coupling constants, 2D NMR correlations, and HPLC and LC/MS characteristics between the synthetic compounds and the metabolite. From extensive comparison of the spectral and chromatographic data of the microsomally derived metabolite and the synthetic compounds, the metabolite has been determined to be the S-(beta)-D-glucuronide of tanaproget.

Animals↗

PubMed2005

Automated accurate mass data processing using a gas chromatograph/time-of-flight mass spectrometer in drug discovery.

A gas chromatograph/time-of-flight (GCT) mass spectrometer, with high mass measurement accuracy to within 5 ppm, has been used for the automated accurate mass analysis of multicomponent mixtures and drug discovery compounds. A multicomponent mixture was analyzed several times over the course of a week to assess the reproducibility and ruggedness of the automated method while operating the GCT in electron ionization mode. For example, the data for 31 radical cations generated via electron ionization was processed using automated software (i.e. OpenLynx) to provide for mass accuracies less than 5 ppm for nearly 100% of the ions from multiple injection data. Mass accuracies of the radical anions of polyaromatic hydrocarbons generated via negative chemical ionization, and protonated pyridines and quinolines generated via methane chemical ionization, were mainly less than 5 ppm from multiple injection data. In addition, the automated method has been used for the accurate mass analysis of drug discovery compounds.

Automation↗

PubMed2005

Integrity profiling of high throughput screening hits using LC-MS and related techniques.

Integrity profiling of HTS hits is valuable for verification of the hit identity and purity. This provides early discovery researchers with more confident SAR theories. Methodology for integrity profiling of HTS hits must be high throughput, consume little material, and selectively provide structure-based data. Analytical techniques that can be utilized for integrity profiling methods are reviewed for their appropriateness in sample preparation, component separation, detection, purity quantitation, identity confirmation, and follow-up.

Chromatography, Liquid↗

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↗