Structural identification of SAR-943 metabolites generated by human liver microsomes in vitro using mass spectrometry in combination with analysis of fragmentation patterns

✍ Scribed by Tobin Strom; Touraj Shokati; Jost Klawitter; Jelena Klawitter; Keith Hoffman; Hans-Martin Schiebel; Uwe Christians

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 313 KB
• Volume: 46
• Category: Article
• ISSN: 1076-5174
• DOI: 10.1002/jms.1930

✦ Synopsis

Abstract

SAR‐943 (32‐deoxo rapamycin) is a proliferation signal inhibitor via interaction with the mammalian target of rapamycin (mTOR). Most importantly, SAR‐943 has improved chemical stability compared to rapamycin (sirolimus) and is currently under investigation as a drug coated on coronary stents. It was the goal of this study to identify the SAR‐943 metabolites generated after incubation with human liver microsomes using high‐resolution mass spectrometry (MS) and MS/iontrap (MS^n^) and comparison of fragmentation patterns of the metabolites with those of SAR‐943 and other known rapamycin derivatives. Our study showed that SAR‐943 is mainly hydroxylated and/or demethylated by human liver microsomes. The structures of the following metabolites were identified: O‐demethylated metabolites: 39‐O‐desmethyl, 16‐O‐desmethyl and 27‐O‐desmethyl SAR‐943; hydroxylated metabolites: hydroxy piperidine SAR‐943, 11‐hydroxy, 12‐hydroxy, 14‐hydroxy, 23‐hydroxy, 24‐hydroxy, 25‐hydroxy, 46‐hydroxy and 49‐hydroxy SAR‐943; didemethylated metabolites: 16,39‐O‐didesmethyl and 27,39‐O‐didesmethyl SAR‐943; demethylated‐hydroxylated metabolites: 39‐O‐desmethyl, 23‐ or 24‐hydroxy and 39‐O‐desmethyl, hydroxy piperidine SAR‐943 and dihydroxylated metabolites: 12‐,23‐ or 24‐dihydroxy SAR‐943. In addition, several other demethylated‐hydroxylated and dihydroxylated metabolites were detected. However, their exact structures could not be identified. Copyright © 2011 John Wiley & Sons, Ltd.