In Vitro Metabolism and Analytical Characterization of SLU-PP-332 and SLU-PP-915: Novel Pan-ERR Agonists With Doping Potential.
This study characterized two novel pan-estrogen-related receptor (ERR) agonists, SLU-PP-332 and SLU-PP-915, which are being investigated as potential "exercise mimetics" — compounds that trigger physiological responses similar to physical exercise. Because of this property, the researchers assessed their relevance for sports anti-doping programs. Using liquid chromatography–high resolution tandem mass spectrometry (LC-HRMS/MS), the team analyzed the chemical profiles of both compounds and mapped their in vitro metabolic transformation products generated via human liver S9 fractions and human liver microsomes. For SLU-PP-332, nine metabolites were identified: six Phase-I and three Phase-II conjugates. For SLU-PP-915, seven Phase-I metabolites were identified. Three SLU-PP-915 metabolites were independently confirmed through chemical synthesis and nuclear magnetic resonance (NMR) spectroscopy. The study is limited to in vitro methodology and does not include in vivo human or animal pharmacokinetic data. The authors suggest these findings could serve as a foundation for developing urine or blood detection methods to identify illicit use of these compounds in competitive sports, but no conclusions about human efficacy or safety are drawn.
Why this grade: The study relies entirely on in vitro metabolic models (human liver S9 fractions and microsomes) with no human subjects or animal experiments, limiting its evidence to analytical and metabolic characterization only.
Rationale Estrogen-related receptor (ERR) agonists such as the drug candidates SLU-PP-332 and SLU-PP-915 are currently being investigated as exercise mimetics, given their ability to trigger human physiological processes similar to those initiated by actual physical activity. This capability prompted the consideration of these compounds as drugs potentially relevant for sports drug testing programs. Methods The two pan-ERR agonists SLU-PP-332 and SLU-PP-915 were characterized using liquid chromatography-high resolution (tandem) mass spectrometry (LC-HRMS/MS). Furthermore, the in vitro metabolic transformation products of both compounds prepared by means of human liver S9 fraction (S9 fraction) and human liver microsomes (HLMs) were analyzed. In addition, selected metabolites of SLU-PP-915 were synthesized and their structures were analyzed by nuclear magnetic resonance (NMR) spectroscopy. Results A total of nine metabolites were identified for SLU-PP-332, consisting of six Phase-I metabolites and three Phase-II conjugates. Conversely, the analysis of SLU-PP-915 yielded only Phase-I transformation products, with a total of seven metabolites identified. In both cases, an in-depth structural elucidation was conducted to obtain a comprehensive overview of the detected metabolites. Furthermore, three metabolites of SLU-PP-915 were confirmed through chemical synthesis and NMR. Conclusion The results obtained in this study gave an in-depth view into the analysis and in vitro metabolism of the newly developed pan-ERR agonists SLU-PP-332 and SLU-PP-915. This may help to uncover the illicit use of these novel compounds as potential performance-enhancing substances.
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