Table 6. Profiles of Compound 10a.
| compound 10 profile | results | |
|---|---|---|
| in vitro activity | enzymatic PI3Kα/β/δ/γ IC50 (nM) | 1.8/271.0/13.9/13.8 |
| PI3Kα/β/δ/γ cellular pAktS473 IC50 (nM)b | 12.1/1393/183/>10000 | |
| DMPK | mouse iv 1 mpk (t1/2, Vd, Cl) | 0.966 h, 0.179 L/kg, 4.16 mL min–1 kg–1 |
| mouse oral 10 mpk (Cmax, DNAUC0–last, F) | 22167 nM, 3090 nM h mg–1 kg–1, 59.4% | |
| rat iv 1 mpk (t1/2, Vd, Cl) | 1.22 h, 0.321 L/kg, 5.28 mL min–1 kg–1 | |
| rat oral 3 mpk (Cmax, DNAUC0–last, F) | 2327 nM, 2711 nM h mg–1 kg–1, 46.9% | |
| ADMET | PPB (human, mouse) | 98.6%, 98.6% |
| permeability 10–6 cm/s (A to B, B to A, efflux ratio) | 2.2, 28.5, 13.1 | |
| MMS remaining (T = 60 min) | 44.6% (h), 32.0% (r), 53.9% (d), 32.7% (m), 13.7% (monkey) | |
| HMS in vivo Clint (mL min–1 kg–1) | 641.9 (m), 58.9 (r), <44 (d), <17.8 (h), <23 (monkey) | |
| hERG IC50 (μM) | 27.5 | |
| CYP (1A2, 2C9, 2C19, 2D6, 3A4) IC50 (μM) | >50, 6.1, 21.6, >50, 23.3 | |
a
Abbreviations: Vd, volume distribution; Cmax, maximum compound concentration in plasma; F, bioavailability; DNAUC0–last, dose-normalized AUC0–last; Cl, clearance; PPB, plasma protein binding; MMS, microsome metabolism stability; HMS, hepatocyte metabolism stability.
b
PI3Kα/β/δ/γ specific cellular acitivities used the BT-474/MDA-MB-468/Jeko-1/RAW264 cell lines.