TABLE 2.
Pharmacokinetic parameters of Compd B and analogs
Brain and plasma exposure were measured in vivo after a single dose of 10 mg/kg administered by oral gavage. Microsomal stability was measured in vitro in mouse and human microsomal preparations.
| Compound | Brain Exposure |
Plasma Exposure |
Microsomal Stability* |
|||
|---|---|---|---|---|---|---|
| Cmax | AUClast | Cmax | AUClast | Mouse | Human | |
| μM | μM*h | μM | μM*h | |||
| Compd B | 0.46 ± 0.16 | 1.23 ± 0.15 | 0.83 ± 0.38 | 2.36 ± 0.25 | 15 (6) | 57 (49) |
| 1 | 0.31 ± 0.01 | 0.08 ± 0.01 | 0.34 ± 0.01 | 0.47 ± 0.02 | 15 (6) | >60 (80) |
| 2 | 0.36 ± 0.08 | 0.94 ± 0.30 | 0.55 ± 0.05 | 1.54 ± 0.44 | 12 (3) | >60 (60) |
| 3 | 0.02 ± 0.00 | 0.03 ± 0.04 | 0.04 ± 0.04 | 0.15 ± 0.11 | 7 (0.1) | >60 (49) |
| 4 | 0.08 ± 0.08 | 0.14 ± 0.11 | 0.05 ± 0.06 | 0.08 ± 0.08 | 11 (2) | >60 (70) |
| 5 | 0.89 ± 0.47 | 1.97 ± 0.43 | 1.36 ± 0.76 | 3.13 ± 0.87 | 20 (12) | >60 (51) |
| 6 | 0.13 ± 0.03 | 0.26 ± 0.07 | 0.11 ± 0.04 | 0.26 ± 0.07 | 16 (7) | >60 (70) |
| 7 | 0.05 ± 0.04 | 0.18 ± 0.12 | 0.05 ± 0.04 | 0.18 ± 0.10 | 16 (7) | 9 (0.9) |
| 8 | 0.03 ± 0.00 | 0.01 ± 0.00 | 0.04 ± 0.01 | 0.06 ± 0.01 | 5 (0.2) | 9 (1) |
| 9 | 0.97 ± 0.03 | 2.35 ± 0.28 | 3.77 ± 0.87 | 7.86 ± 1.46 | 29 (24) | >60 (54) |
| 10 | 6.12 ± 1.75 | 16.8 ± 0.52 | 2.53 ± 0.85 | 7.59 ± 0.76 | 21 (14) | >60 (80) |
| 11 | 1.28 ± 0.11 | 5.97 ± 0.83 | 0.87 ± 0.12 | 3.74 ± 0.04 | 21 (15) | >60 (81) |
| 12 | 1.14 ± 0.03 | 4.83 ± 0.95 | 0.71 ± 0.06 | 3.13 ± 0.67 | 17 (9) | >60 (81) |
| 13 | 2.74 ± 0.65 | 13.5 ± 0.23 | 1.20 ± 0.78 | 6.10 ± 0.26 | 18 (11) | >60 (87) |
| 14 | 0.46 ± 0.38 | 0.88 ± 0.32 | 0.16 ± 0.13 | 0.33 ± 0.10 | 7 (0.4) | >60 (74) |
| 15 | 0.28 ± 0.17 | 0.48 ± 0.14 | 0.10 ± 0.06 | 0.30 ± 0.06 | 11 (3) | 36 (33) |
| 16 | 5.16 ± 2.93 | 18.7 ± 5.69 | 6.39 ± 3.10 | 23.9 ± 6.23 | >60 (70) | >60 (94) |
| 17 | 2.86 ± 0.35 | 6.61 ± 0.01 | 1.54 ± 0.56 | 4.09 ± 0.61 | 24 (18) | >60 (79) |
| 18 | 1.09 ± 0.11 | 4.22 ± 0.71 | 1.05 ± 0.11 | 3.90 ± 0.89 | 25 (20) | >60 (63) |
*
Half-life in minutes and percentage remaining after 60-minute incubation.
Cmax, maximum peak drug concentration; AUClast, area under the time concentration curve from time zero to time of last measurable concentration.