AstraZeneca metabolite identification (MetID) schemes for 120 compounds

Metabolite identification schemes to support Metabolite Identification Data in Drug Discovery, Part 1: Data Generation and Trend Analysis Marie Ahlqvist,1 Isabella Bonner Karlsson,1 Anja Ekdahl,1 Cecilia Ericsson,1 Ulrik Jurva,1 Filip Miljković,2,* Ya Chen,2,3 and Susanne Winiwarter1,* Mol. Pharmaceutics. 2025, https://doi.org/10.1021/acs.molpharmaceut.5c00738 1Drug Metabolism and Pharmacokinetics, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, 431 83 Mölndal, Sweden 2Medicinal Chemistry, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, 431 83 Mölndal, Sweden 3Department of Pharmaceutical Sciences, Division of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, 1090 Vienna, Austria *Corresponding Authors Filip Miljković, Phone: +46-73-699-3320, E-mail: [email protected], ORCID: 0000-0001-5365-505X. Susanne Winiwarter, Phone: +46-31-7064913, E-mail: [email protected], ORCID: 0000-0002-9808-1683. This file contains metabolite identification schemes for 120 compounds, derived from incubations in human hepatocytes (Gender: Pooled, Hepatocyte Concentration: 1 million cells/mL, Compound Concentration: 4 µM, Incubation Time: 120 min). Compound 1: Parent remaining 96% Compound 2: Parent remaining 80% F NNH N OO O F NNH N OO O[+O] F NNH N OH F NNH N OOH O M1 9%, Hydroxylation M3 1%, O-demethylation M2 8%, Ester hydrolysis Cmpd 2, 80% Compound 3: Parent remaining 90% Compound 4: Parent remaining 60% Compound 5: Parent remaining 60% Compound 6: Parent remaining 99% Compound 7: Parent remaining 89% Compound 8: Parent remaining 34% Compound 15: Parent remaining 84% O N O N N N NN H2 O N O N N N NN H2 [+O] O N O N N N NN H2 [+O] O N O N N N N N H2 [+O] O N O N N N NN H2[+H2O] O N O N N N NN H2 O N-oxidation, 4% Hydroxylation + Desaturation, 3% Impurity (+O), also present at 0 min, 2% Cmpd 15, 84% Impurity (+H2O), also present at 0 min, 3% Compound 16: Parent remaining 62% NH N OH NH O N N CH3 F F F NH N O NH O N N CH3 F F F NH N O NH O N N CH3 F F F OH NH N O NH O N N CH3 F F F [+176] [+O] NH N O NH O N N CH3 F F F OH NH N O NH O N N CH3 F F F OH M2, 10% Reduction. Seen as -16 due to loss of water. M5, 2% Hydroxylation + Glucuronidation M1, 16% Hydroxylation M3, 7% Hydroxylation Cmpd 16, 62% M4, 3% Hydroxylation Compound 17: Parent remaining 51% Compound 18: Parent remaining 92% Compound 19: Parent remaining 99% Compound 20: Parent remaining 96% Compound 21: Parent remaining 58% + 15% + 3% Compound 22: Parent remaining 54% + 7% + 4% Compound 23: Parent remaining 85% Compound 24: Parent remaining 68% Compound 31: Parent remaining 73% Compound 32: Parent remaining 85% Compound 33: Parent remaining 95% Compound 34: Parent remaining 61% Compound 35: Parent remaining 78% Compound 36: Parent remaining 100% Compound 37: Parent remaining 78% Compound 38: Parent remaining 95% Compound 39: Parent remaining 97% Compound 40: Parent remaining 99% Compound 47: Parent remaining 91% Compound 48: Parent remaining 90% Compound 49: Parent remaining 94% Compound 50: Parent remaining 90% Compound 51: Parent remaining 94% N N OH CH3 CH3 O Cl N N CH3 CH3 O Cl O O OH OH OH O OH N NH OH CH3 CH3 O Cl OHO Ring opening, 5% Cmpd 51, 94% Glucuronide conjugation, 1% Compound 52: Parent remaining 79% N NH OH CH3 O F F CH3 CH3 OOH [+O] N N+ OH CH3 O F F CH3 CH3 O– NH N OH O F F CH3 CH3 N NH OH CH3 O F F CH3 CH3 OH N NH OH CH3 O F F CH3 CH3 OOH N N OH CH3 O F F CH3 CH3 [+O] N N OH CH3 O F F CH3 CH3 Ring opening, 0.9% N-Oxidation, 1% N-Demethylation, 0.8% Cmpd 52, 79% Hydroxylation, 4% Ring opening, 7% Hydroxylation & ring opening, 0.8% Compound 53: Parent remaining 90% N NH CH3 CH3 OH H O F N N N CH3 CH3 H CH3 O F N O O OH OH OH O OH N+ N CH3 CH3 OH H CH3 O F N O– NH N CH3 CH3 OH H CH3 O F N OH NH N CH3 CH3 OH H CH3 O F N O OH N N CH3 CH3 OH H CH3 O F N Glucuronide conjugation, trace Ring opening, 7% Ring opening, 1% N-Demethylation, 1% Cmpd 53, 90% N-Oxidation, 0.7% Compound 54: Parent remaining 99% Compound 55: Parent remaining 97% N N OH CH3 O N N NH OH CH3 O N O OH N N OH CH3 O N [+O] N N CH3 O N O O OH OH OH O OH Hydroxylation, 0.6% Glucuronide conjugation, 0.3% Cmpd 55, 97% Ring opening, 2% Compound 56: Parent remaining 91% NCH3 O N H N F O CH3 O NCH3 O N H N F O CH3 O O O O H O H O H OH NCH3 O H N H2 N F O CH3 NCH3 O H N H2 N F O CH3 O O OH O H O H OH M2, 2% M3, <1% Cmpd 56, 91% M1, 4% Compound 63: Parent remaining 90% CH3 O N O N OH O F CH3 CH3 F F F CH3 O N O N OH O F CH3 CH3 F F F [+O] CH3 O N OH N OH O F CH3 CH3 F F F CH3 O N O N O O F CH3 CH3 F F F O OH OH OH OH O CH3 O N O N OH O F CH3 CH3 F F F [-2H] Hydroxylation Ketone reduction Glucuronide Cmpd 63, 90% Desaturation Compound 64: Parent remaining 91% CH3 ON O N N O O CH3 N CH3 OH CH3 ON O N N O OH N CH3 OH CH3 ON O N N O O CH3 N CH3 OH [-H2] CH3 ON O N N O O N CH3 OH SO O OH M1, 5% M2, 2% Cmpd 64, 91% M3, 1% Compound 65: Parent remaining 86% N OH CH3 O N O O N N O CH3 N OH CH3 O N O O N N OH N OH CH3 O N O O N N O SO O OH N OH CH3 O N O O N N O CH3 [+O] N+ OH CH3 O N O O N N O CH3 O– N O CH3 O N O O N N O CH3 O OH OH OH OH O M2, 2% M3, <1% M4, <1% M5, <1% Cmpd 65, 86% M1, 10% Compound 66: Parent remaining 98% Compound 67: Parent remaining 54% Compound 68: Parent remaining 93% Compound 69: Parent remaining 57% Compound 70: Parent remaining 61% Compound 71: Parent remaining 87% Compound 72: Parent remaining 92% Compound 79: Parent remaining 52% Compound 80: Parent remaining 90% Compound 81: Parent remaining 70% Compound 82: Parent remaining 73% Compound 83: Parent remaining 96% Compound 84: Parent remaining 66% Compound 85: Parent remaining 66% Compound 86: Parent remaining 93% Compound 87: Parent remaining 61% Compound 88: Parent remaining 87% Compound 95: Parent remaining 51% Compound 96: Parent remaining 96% Compound 97: Parent remaining 98% Compound 98: Parent remaining 96% Compound 99: Parent remaining 91% Compound 100: Parent remaining 86% Compound 101: Parent remaining 86% Compound 102: Parent remaining 51% Compound 103: Parent remaining 98% Compound 104: Parent remaining 96% Compound 111: Parent remaining 76% Compound 112: Parent remaining 61% Compound 113: Parent remaining 35% Compound 114: Parent remaining 0% Compound 115: Parent remaining 83% Compound 116: Parent remaining 92% Compound 117: Parent remaining 78% Compound 118: Parent remaining 88% Compound 119: Isomer 1, Parent remaining 61% Cmpd 119, 61% N N OH CH3 CH3 N ON CH3 CH3 CH3 N N OH CH3 CH3 N O CH3 CH3 CH3 O OH O OH OH OH dealkylation N N OH CH3 CH3 N OH CH3 CH3 CH3 Glucuronidation N N OH CH3 CH3 N ON CH3 CH3 CH3 OH Hydroxylation Hydroxylation N N OH CH3 CH3 N ON CH3 CH3 CH3 OH N N OH CH3 CH3 N ON CH3 CH3 CH3 O Alkohol ox to aldehyde (-2e-, -2H+) M1, 12% M3, 13% M4, 2% M5, 2% M2, 10% Compound 120: Isomer 2, Parent remaining: 17% Cmpd 120, 17% N N OH CH3 CH3 N ON CH3 CH3 CH3 N N OH CH3 CH3 N O CH3 CH3 CH3 O OH O OH OH OH dealkylation N N OH CH3 CH3 N OH CH3 CH3 CH3 Glucuronidation N N OH CH3 CH3 N ON CH3 CH3 CH3 OH Hydroxylation Hydroxylation N N OH CH3 CH3 N ON CH3 CH3 CH3 OH N N OH CH3 CH3 N ON CH3 CH3 CH3 O Alkohol ox to aldehyde (-2e-, -2H+) M1, 3% M3, 3% M4, 27% M5, 48% M2, <1%