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Drug Metabolism and Pharmacokinetics of 4-Substituted Methoxybenzoyl-Aryl-Thiazoles (SMART).

06:00 EDT 3rd August 2010 | BioPortfolio

Summary of "Drug Metabolism and Pharmacokinetics of 4-Substituted Methoxybenzoyl-Aryl-Thiazoles (SMART)."

Tubulins are one of the oldest and most extensively studied therapeutic targets for cancer. Although many tubulin polymerizing and depolymerizing agents are known, the search for improved agents continues. We screened a class of tubulin targeting small molecules, and identified 4-(3,4,5-trimethoxylbenzoyl)-2-phenyl-thiazole (SMART-H) as our lead compound. SMART-H inhibited the proliferation of a variety of cancer cells in vitro, at sub-nanomolar IC50, and in vivo, in nude mice xenografts, with near 100% tumor growth inhibition. Metabolic stability studies with SMART-H in liver microsomes of four species (mouse, rat, dog, and human) revealed half-lives between < 5 and 30 min, demonstrating an inter-species variability. The clearance predicted based on in vitro data correlated well with in vivo clearance obtained from mouse, rat, and dog in vivo pharmacokinetic studies. SMART-H underwent four major metabolic processes, including ketone reduction, demethylation, combination of ketone reduction and demethylation, and hydroxylation in human liver microsomes. Metabolite identification studies revealed that the ketone and the methoxy groups of SMART-H were most labile, and that ketone reduction was the dominant metabolism reaction in human liver microsomes. We designed and tested four derivatives of SMART-H to improve the metabolic stability. The oxime and hydrazide derivatives, replacing the ketone site, demonstrated a 2-3-fold improved half-life in human liver microsomes, indicating that our prediction regrading metabolic stability of SMART-H can be extended by blocking ketone reduction. These studies led us to the next generation of SMART compounds with greater metabolic stability and higher pharmacologic potency.

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1 GTx Inc.;

Journal Details

This article was published in the following journal.

Name: Drug metabolism and disposition: the biological fate of chemicals
ISSN: 1521-009X
Pages:

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