TABLE 4
Relevant metabolites of SB-649868 in human plasma, urine, and feces after a single oral administration of [14C]SB-649868 at a target dose of 30 mg
| Matrix (Mean % Dose) | Proposed Structure | Parent Ion [M + H]+ (m/z) | [M + H]+ Ion and MS/MS Product Ions | 1H-NMR (600 MHz, 1:1 Acetonitrile:D2O) (Where Available) |
|---|---|---|---|---|
| PL |  SB-649868 | 478 (P) | 478 [M + H]+ | 7.83 (d, 1H), 7.68 (dd, 1H), 7.56 (dd, 1H), 7.37 (dd, 2H), 7.37 (t, 1H), 7.11 (d, 1H), 7.04 (dd, 2H), 5.00 (m, 1H), 3.71 (dd, 1H), 3.31 (dm, 1H), 3.25 (dd, 1H), 2.97 (tt, 1H), 2.17 (s, 3H), 1.72 (dm, 1H), 1.61 (dm, 1H), 1.55 (tm, 1H), 1.47 m, 2H), 0.83, m, 1H) |
| UR (BQL) | 460, 317, 316, 242, 241, 220, 145, 98 | Signals doubled because of rotamers, major subspectrum quoted | ||
| FE (BQL) | ||||
| PL |  Amine (M8) | 334 (P − 144) | 334 [M + H]+ | 7.39 (dd, 2H), 6.98 (t, 2H), 2.70 (s, 3H) |
| UR (0.6) | 317, 316, 220, 98 | Other resonances obscured | ||
| FE (1.5) | ||||
| UR (0.3) |  Benzofuran dihydrodiol (M20, M21) | 512 (P + 34) | 512 [M + H]+ | No NMR |
| FE (6.2) | 476, 317, 257, 239, 220 | |||
| PL |  Benzofuran ring-opened carboxylic acid (GSK2329158, M25) | 512 (P + 2 + 16 + 16) | 512 [M + H]+ | 7.46 (dd, 2H), 7.42 (dd, 2H), 7.22 (t, 1H), 7.20 (t, 1H), 7.16 (dd, 2H), 7.05 (dd, 1H), 7.01 (dd, 2H),7.01 (dd, 1H), 7.00 (dd, 1H), 6.97 (dd, 1H), 4.98 (m, 1H), 4.44 (dm, 1H), 3.86 (m, 1H), 3.71 (d, 1H), 3.70 (dd, 1H), 3.69 (dd, 1H), 3.65 (d, 1H), 3.64 (s, 2H), 3.54 (dd, 1H), 3.32 (dm, 1H), 3.23 (dd, 1H), 3.17 (td, 1H), 2.95 (td, 1H), 2.67 (s, 3H), 2.42 (s, 3H), 1.7–1.8 (m, 2H), 1.4–1.7 (m, 6H), 1.2–1.4 (m, 2H), 0.95 (m, 1H), 0.86 (m, 1H) |
| UR (1.5) | 494, 334, 317, 316, 257, 220 | 1:1 rotameric subspectra observed, both quoted. | ||
| FE (10.3) | ||||
| UR (BQL) |  Piperidine ring-opened carboxylic acid (M32) | 510 (P + 32) | 510 [M + H]+ | No NMR |
| FE (1.1) | 492, 348, 330, 317, 274, 273, 220, 145 | |||
| UR (1.6) |  Benzofuran ring-opened carboxylic acid glucuronide (M41) | 688 (P + 176 + 16 + 16 + 2) | 688 [M + H]+ | No NMR |
| 670, 626, 512, 468, 450, 355, 275 | ||||
| UR (0.6) |  Benzofuran hydroxy (M86) | 494 (P + 16) | 494 [M + H]+ | 7.58 (dd, 2H), 7.37 (dd, 2H), 6.56 (s, 1H), 4.98 (m, 1H) |
| 476, 317, 316, 258, 257, 220, 98 | Other resonances obscured 13C: benzofuran 3-carbon 101.2 ppm | |||
| FE (0.7) |  Oxygenated (M90) | 494 (P + 16) | 494 [M + H]+ | No NMR |
| 333, 220 | ||||
| UR (BQL) |  Dehydrated hemiaminal (M94) | 478 (P + 0) | 478 [M + H]+ | 7.62 (dd, 1H), 7.36 (t, 1H), 7.29 (dd, 2H), 7.14 (dd, 1H), 7.08 (dd, 2H), 6.96 (d, 1H), 6.83 (d, 1H), 4.46 (dm, 1H), 4.25 (dd, 1H), 4.09 (m, 1H), 3.80 (dd, 1H), 3.12 (dd, 1H), 2.02 (s, 3H), 1.64 (dm, 1H), 1.50 (qm, 1H), 1.43 (dm, 1H), 1.42 (dm, 1H), 1.26 (m, 1H), 0.56 (m, 1H) |
| FE (0.7) | 317, 249, 242, 241, 220, 162 | |||
| UR (1.2) |  Benzofuran dihydrodiol or ring opened carboxylic acid glucuronide (M95) | 688 (P + 176 + 16 + 16 + 2) | 688 [M + H]+ | No NMR |
| 293, 276 | ||||
| PL |  Hemiaminal (GSK2329163, M98) | 496 (P + 18) | 496 [M + H]+ | 7.40 (dd, 2H), 7.32 (dd, 1H), 7.20 (t, 1H), 7.19 (dd, 2H), 7.05 (dd, 1H), 4.93 (dd, 1H), 4.43 (dm, 1H), 3.95 (m, 1H), 3.57 (dd, 1H), 3.37 (dd, 1H), 3.22 (dd, 1H), 3.10 (dd, 1H), 2.92 (td, 1H), 2.02 (s, 3H), 1.69 (dm, 1H), 1.43 (qm, 1H), 1.34 (dm, 1H), 1.28 (dm, 1H), 1.18 (m, 1H), 0.25 (m, 1H) |
| UR (0.2) | MS/MS of [M-H2O + H]+ mion: 478 317, 285, 249, 241, 220 | 7.40 (dd, 2H), 7.32 (dd, 1H), 7.20 (t, 1H), 7.19 (dd, 2H), 7.05 (dd, 1H), 4.93 (dd, 1H), 4.43 (dm, 1H), 3.95 (m, 1H), 3.57 (dd, 1H), 3.37 (dd, 1H), 3.22 (dd, 1H), 3.10 (dd, 1H), 2.92 (td, 1H), 2.02 (s, 3H), 1.69 (dm, 1H), 1.43 (qm, 1H), 1.34 (dm, 1H), 1.28 (dm, 1H), 1.18 (m, 1H), 0.25 (m, 1H) | ||
| FE (2.61) | ||||
| UR (0.3) |  Oxygenated benzofuran dihydrodiol or ring-opened carboxylic acid (M99) | 528 (P + 16 + 34) | 528 [M + H]+ | No NMR |
| FE (3.6) | 510, 492, 333, 332, 299, 257, 236 | |||
| FE (1.3) |  Oxygenated benzofuran dihydrodiol or ring-opened carboxylic acid (M100) | 528 (P + 16 + 34) | 528 [M + H]+ | No NMR |
| 333, 332 MS/MS of [M-H2O + H]+528 m333, 332, 317, 315, 220 | ||||
| FE (2.61) |  Hydrated (M101) | 496 (P + 18) | 496 [M + H]+ | No NMR |
| MS/MS of [M-H2O + H]+478 317, 241, 220 | ||||
| FE (2.4) |  Oxygenated benzofuran dihydrodiol or ring-opened carboxylic acid (M102) | 528 (P + 16 + 34) | 528 [M + H]+ | No NMR |
| MS/MS of [M-H2O + H]+510 333, 249, 241, 220 |
PL, plasma; UR, urine; FE, feces; BQL, below limit of quantification; P, parent.
a M98 and M101 coelute during HPLC analysis.