Me aboli e iden i ica ion schemes o suppo
Me aboli e Iden i ica ion Da a in D ug Disco e y, Pa 1: Da a
Gene a ion and T end Analysis
Ma ie Ahlq is ,1 Isabella Bonne Ka lsson,1 Anja Ekdahl,1 Cecilia E icsson,1
Ul ik Ju a,1 Filip Miljko ić,2,* Ya Chen,2,3 and Susanne Winiwa e 1,*
Mol. Pha maceu ics. 2025, h ps://doi.o g/10.1021/acs.molpha maceu .5c00738
1D ug Me abolism and Pha macokine ics, Resea ch and Ea ly De elopmen , Ca dio ascula ,
Renal and Me abolism (CVRM), BioPha maceu icals R&D, As aZeneca, 431 83 Mölndal,
Sweden
2Medicinal Chemis y, Resea ch and Ea ly De elopmen , Ca dio ascula , Renal and Me abolism
(CVRM), BioPha maceu icals R&D, As aZeneca, 431 83 Mölndal, Sweden
3Depa men o Pha maceu ical Sciences, Di ision o Pha maceu ical Chemis y, Facul y o Li e
Sciences, Uni e si y o Vienna, 1090 Vienna, Aus ia
*Co esponding Au ho s
Filip Miljko ić, Phone: +46-73-699-3320, E-mail: ilip.miljko ic@as azeneca.com,
ORCID: 0000-0001-5365-505X.
Susanne Winiwa e , Phone: +46-31-7064913, E-mail: susanne.winiwa e @as azeneca.com,
ORCID: 0000-0002-9808-1683.
This ile con ains me aboli e iden i ica ion schemes o 120 compounds, de i ed om incuba ions
in human hepa ocy es (Gende : Pooled, Hepa ocy e Concen a ion: 1 million cells/mL, Compound
Concen a ion: 4 µM, Incuba ion Time: 120 min).
Compound 1: Pa en emaining 96%
Compound 2: Pa en emaining 80%
F
NNH
N
OO
O
F
NNH
N
OO
O[+O]
F
NNH
N
OH
F
NNH
N
OOH
O
M1 9%, Hyd oxyla ion
M3 1%, O-deme hyla ion
M2 8%, Es e hyd olysis
Cmpd 2, 80%
Compound 3: Pa en emaining 90%
Compound 4: Pa en emaining 60%
Compound 5: Pa en emaining 60%
Compound 6: Pa en emaining 99%
Compound 7: Pa en emaining 89%
Compound 8: Pa en emaining 34%
Compound 15: Pa en emaining 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-oxida ion, 4%
Hyd oxyla ion + Desa u a ion, 3%
Impu i y (+O), also p esen a 0 min, 2%
Cmpd 15, 84%
Impu i y (+H2O), also p esen a 0 min, 3%
Compound 16: Pa en emaining 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%
Reduc ion. Seen as -16 due o
loss o wa e .
M5, 2%
Hyd oxyla ion + Glucu onida ion
M1, 16%
Hyd oxyla ion
M3, 7%
Hyd oxyla ion
Cmpd 16, 62%
M4, 3%
Hyd oxyla ion
Compound 17: Pa en emaining 51%
Compound 18: Pa en emaining 92%
Compound 19: Pa en emaining 99%
Compound 20: Pa en emaining 96%
Compound 21: Pa en emaining 58% + 15% + 3%
Compound 22: Pa en emaining 54% + 7% + 4%
Compound 23: Pa en emaining 85%
Compound 24: Pa en emaining 68%
Compound 31: Pa en emaining 73%
Compound 32: Pa en emaining 85%
Compound 33: Pa en emaining 95%
Compound 34: Pa en emaining 61%
Compound 35: Pa en emaining 78%
Compound 36: Pa en emaining 100%
Compound 37: Pa en emaining 78%
Compound 38: Pa en emaining 95%
Compound 39: Pa en emaining 97%
Compound 40: Pa en emaining 99%
Compound 47: Pa en emaining 91%
Compound 48: Pa en emaining 90%
Compound 49: Pa en emaining 94%
Compound 50: Pa en emaining 90%
Compound 51: Pa en emaining 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%
Glucu onide conjuga ion, 1%
Compound 52: Pa en emaining 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-Oxida ion, 1%
N-Deme hyla ion, 0.8%
Cmpd 52, 79%
Hyd oxyla ion, 4%
Ring opening, 7%
Hyd oxyla ion & ing opening, 0.8%
Compound 53: Pa en emaining 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
Glucu onide conjuga ion, ace
Ring opening, 7%
Ring opening, 1%
N-Deme hyla ion, 1%
Cmpd 53, 90%
N-Oxida ion, 0.7%
Compound 54: Pa en emaining 99%
Compound 55: Pa en emaining 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
Hyd oxyla ion, 0.6%
Glucu onide conjuga ion, 0.3%
Cmpd 55, 97%
Ring opening, 2%
Compound 56: Pa en emaining 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: Pa en emaining 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]
Hyd oxyla ion
Ke one educ ion
Glucu onide
Cmpd 63,
90%
Desa u a ion
Compound 64: Pa en emaining 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: Pa en emaining 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: Pa en emaining 98%
Compound 67: Pa en emaining 54%
Compound 68: Pa en emaining 93%
Compound 69: Pa en emaining 57%
Compound 70: Pa en emaining 61%
Compound 71: Pa en emaining 87%
Compound 72: Pa en emaining 92%
Compound 79: Pa en emaining 52%
Compound 80: Pa en emaining 90%
Compound 81: Pa en emaining 70%
Compound 82: Pa en emaining 73%
Compound 83: Pa en emaining 96%
Compound 84: Pa en emaining 66%
Compound 85: Pa en emaining 66%
Compound 86: Pa en emaining 93%
Compound 87: Pa en emaining 61%
Compound 88: Pa en emaining 87%
Compound 95: Pa en emaining 51%
Compound 96: Pa en emaining 96%
Compound 97: Pa en emaining 98%
Compound 98: Pa en emaining 96%
Compound 99: Pa en emaining 91%
Compound 100: Pa en emaining 86%
Compound 101: Pa en emaining 86%
Compound 102: Pa en emaining 51%
Compound 103: Pa en emaining 98%
Compound 104: Pa en emaining 96%
Compound 111: Pa en emaining 76%
Compound 112: Pa en emaining 61%
Compound 113: Pa en emaining 35%
Compound 114: Pa en emaining 0%
Compound 115: Pa en emaining 83%
Compound 116: Pa en emaining 92%
Compound 117: Pa en emaining 78%
Compound 118: Pa en emaining 88%
Compound 119: Isome 1, Pa en emaining 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
dealkyla ion
N
N
OH CH3
CH3
N
OH
CH3
CH3
CH3
Glucu onida ion
N
N
OH CH3
CH3
N
ON
CH3
CH3
CH3
OH
Hyd oxyla ion
Hyd oxyla ion
N
N
OH CH3
CH3
N
ON
CH3
CH3
CH3
OH
N
N
OH CH3
CH3
N
ON
CH3
CH3
CH3
O
Alkohol ox o aldehyde
(-2e-, -2H+)
M1, 12%
M3, 13%
M4, 2% M5, 2%
M2, 10%
Compound 120: Isome 2, Pa en emaining: 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
dealkyla ion
N
N
OH CH3
CH3
N
OH
CH3
CH3
CH3
Glucu onida ion
N
N
OH CH3
CH3
N
ON
CH3
CH3
CH3
OH
Hyd oxyla ion
Hyd oxyla ion
N
N
OH CH3
CH3
N
ON
CH3
CH3
CH3
OH
N
N
OH CH3
CH3
N
ON
CH3
CH3
CH3
O
Alkohol ox o aldehyde
(-2e-, -2H+)
M1, 3%
M3, 3%
M4, 27% M5, 48%
M2, <1%
