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Compound Property Optimization in Drug Discovery Using Quantitative Surface Sampling Micro Liquid Chromatography with Tandem Mass Spectrometry

Chen, Xiao-Hui and Hatsis, Panagiotis and Judge, Joyce and Argikar, Upendra and Ren, Xiaojun and Sarber, Jason and Mansfield, Keith and Liang, Guiqing and Adamal, Adam and Catoire, Alexandre and Bentley, Adam and Ramos, Luis and Moench, Paul and Hintermann, Samuel and Carcache, David and Glick, Jim and Flarakos, Jimmy (2016) Compound Property Optimization in Drug Discovery Using Quantitative Surface Sampling Micro Liquid Chromatography with Tandem Mass Spectrometry. Analytical Chemistry, 88 (23). pp. 11813-11820. ISSN 0003-27001520-6882

Abstract

Surface sampling micro liquid chromatography tandem mass spectrometry (SSµLC-MS/MS) was explored as a quantitative tissue distribution technique for probing compound properties in drug discovery. A method was developed for creating standard curves using surrogate tissue sections from blank tissue homogenate spiked with compounds. The resulting standard curves showed good linearity and high sensitivity. The accuracy and precision of standards met acceptance criteria of ± 30%. A new approach was proposed based on an experimental and mathematical method for tissue extraction efficiency evaluation by means of consecutively sampling a location on tissue twice by SSµLC-MS/MS. The observed extraction efficiency ranged from 69% to 82% with acceptable variation for the test compounds. Good agreement in extraction efficiency was observed between surrogate tissue sections and incurred tissue sections. This method was successfully applied to two case studies in which tissue distribution was instrumental in advancing project teams’ understanding of compound properties.

Item Type: Article
Date Deposited: 09 Feb 2017 00:45
Last Modified: 09 Feb 2017 00:45
URI: https://oak.novartis.com/id/eprint/29751

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