Table 1.
(A) Microsome (oxidative metabolism) stability studies revealed a short half-life (T1/2) and high clearance (CL) of 1154 in liver microsome assays. Longer T1/2 and lower CL renders 792 stable with respect to oxidative metabolism. (B) Studies of time-dependent inhibition of CYP-3A4 showed none associated with 792, and a moderate effect with 1154.
| A. Microsome (Oxidative) Stability | |||||||
|---|---|---|---|---|---|---|---|
| Tricyclic Class | Compound ID | T1/2 (min) | CL (µL/min/mg) | ||||
| Mouse | Rat | Human | Mouse | Rat | Human | ||
| Subst. Carbazole | ATUX-792 | >256 | >256 | >256 | <5 | <5 | <5 |
| Dibenzoazepine | DBK-1154 | 6 | 3 | 10 | 234 | 521 | 134 |
| ID = Identification, T1/2 = Half-life, CL = Clearance, Subst.= Substituted | |||||||
| B. CYP-3A4 Time Dependent Inhibition | |||||||
| Tricyclic Class | Compound ID | IC50 * (µM) at Pre-incubation time | IC50 Shift | ||||
| 5 min | 30 min | 60 min | 5/60 min | ||||
| Subst. Carbazole | ATUX-792 | >50 | >50 | >50 | NA | ||
| Dibenzoazepine | DBK-1154 | 42 | 27 | 18 | 2.4 | ||
ID = Identification, Subst = Substituted, min = minutes. * Concentration required for 50% inhibition of midazolam (a CYP-A4 substrate) turnover.