Drug discovery metabolic stability

Metabolic stability in human liver preparations may represent a suitable experimental tool to obtain relevant pharmacokinetic information in an early phase of drug discovery. Compounds which are metabolized principally by the liver can be identified and studied in more detail to determine the principal sites of biotransformation. 

Chovan, L.E. et al. 2004. Automatic mass spectrometry method development for drug discovery Application in metabolic stability assays. Rapid Commun. Mass Spectrom. 18 3105. 

The are several clearance and toxicological aspects that have to be considered in the drug discovery process such as metabolic stability, enzyme selectivity, CYP inhibition and type of inhibition. Among these factors, the prediction of the site of metabolism has become one of the most successful parameters for prediction. The knowledge of the site of metabolism enhances the opportunity to chemically modify the molecule to improve the metabolic stability. There are several approaches based on database mining, chemical reactivity, protein interaction or both that have been developed for the prediction of this property, with different degree of success and applicability. 

Rourick, R. A., Jenkins, K. M., Walsh, J., Xu, R., Cai, Z. and Kassel, D. B., Integration of Custom LC/MS Automated Data Processing Strategies for the Rapid Assessment of Metabolic Stability and Metabolic Identification in Drug Discovery, American Society for Mass Spectrometry 2002 Conference Abstract, Orlando, FL, USA, 2002. 

Thompson, T. N. Early ADME in support of drug discovery the role of metabolic stability studies. Curr Drug Metab 2000, 1, 215-241. 

Baranczewski, P, Stanczak, A., Sundberg, K., Svensson, R., Wallin, A., Jansson, J., Garberg, P., Postlind, H. Introduction to in vitro estimation of metabolic stability and drug interactions of new chemical entities in drug discovery and development. Pharmacol. Rep. 2006, 58, 453-72. 

Cyprotex, using Cloe Screen , evaluates pharmacokinetic properties in vitro and establishes a broad portfolio of in vitro assays that allows researchers to investigate the metabolism parameters for drug discovery and development. This company supplies the following data and assays (276) microsomal stability,... 

Drug discovery Lead candidate Screening Protein identification natural products identification metabolic stability profiles molecular weight determination for combinatorial/ medicinal chemistry support. 

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