Screening and structural characterization of reactive metabolites, as one of the major efforts to reduce attrition in drug development, has increasingly become an integral part of the ADMET-guided lead optimization process in drug discovery.
2 Yan Z, Maher N, Torres R, Caldwell GW and Huebert N (2005) Rapid Commun Mass Spectrom 19; 3322-3330
Assay Design | Test article incubated with human liver microsomes and glutathione in the presence and absence of NADPH |
---|---|
Test Article Concentration | 50 µM |
Microsomal Concentration | 1 mg/mL |
Glutathione Concentration | 1 mM |
Quality Controls | Minus NADPH (negative control) Ticlopidine (positive control) |
Test Article Requirements | 100 µL of 10 mM DMSO solution or equivalent amount of solid compound. |
Analysis Method | High resolution accurate mass Q-TOF |
Data Delivery | Summary report including:
Comprehensive report (optional) |
Name | Formula | Mass Difference | m/z | Mass error (ppm) | Identifier | RT (min) | Neutral loss |
---|---|---|---|---|---|---|---|
Parent | C14H14ClNS | - | 264.0618 | 1.7 | - | 3.23 | - |
GSH + reduction | C24H31ClN4O6S2 | +307.0830 | 571.1443 | -1.5 | M1 | 2.67 | 307 |
GSH + hydration | C24H31ClN4O7S2 | +323.0790 | 587.1404 | 0.6 | M2 | 2.45 | 75, 129, 307 |
GSH + hydration | C24H31ClN4O7S2 | +323.0785 | 587.1398 | -0.5 | M3 | 2.52 | 129, 307 |
1 Evans DC et al. (2004) Drug−protein adducts: An industry perspective on minimizing the potential for drug bioactivation in drug discovery and development. Chem Res Toxicol 17(1); 3-16
2 Yan Z et al. (2005) Rapid detection and characterization of minor reactive metabolites using stable-isotope trapping in combination with tandem mass spectrometry. Rapid Commun Mass Spectrom 19(22); 3322-3330
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