Pharmacokinetic parameters of novel analogs (13–19) in CD-1 mouse, Sprague-Dawley (SD) rats, and cynomolgus monkeys.
| PK parameters | Compound | |||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| (13) | (15) | CEP-28122 (17) | CEP-37440 (19) | |||||||||
| SCID mouse | Rat | Dog | S-D rat | CD-1 mouse | CD-1 mouse | Rat | Dog | Mo | CD-1 mouse | SD rat | Mo | |
| iv | ||||||||||||
| Dose (mg kg−1) | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 | 1.0 |
| t 1/2 (h) | 0.3 | 0.8 | 1.1 | 0.80 ± 0.05 | 0.7 | 0.7 | 0.9 ± 0.2 | 2.4 ± 0.2 | 1.2 ± 0.05 | 3.0 | 2 ± 0.4 | 5.4 ± 0.6 |
| Cl (mL min−1 kg−1) | 37 | 13 | 22 | 16 ± 1.5 | 20 | 29 | 17 ± 2 | 40 ± 1 | 28 ± 4 | 10 | 4 ± 0.2 | 30.±0.5 |
| % Cl/hepatic blood flow | 41 | 20 | 58 | — | — | — | — | — | — | — | — | — |
| V d (L kg−1) | 0.9 | 0.9 | 2.1 | 1.1 ± 0.1 | 1.2 | 1.8 | 1.3 ± 0.2 | 8.2 ± 0.5 | 2.9 ± 0.3 | 2.7 | 0.8 ± 0.2 | 13.2 ± 1.9 |
| AUC0−∞ (ng h mL−1) | 446 | 1276 | 773 | 1019 ± 91 | 830 | 584 | 989 ± 127 | 409 ± 16 | 615 ± 89 | 1612 | 4005 ± 237 | 554 ± 11 |
| Po | ||||||||||||
| Dose (mg kg−1) | 10.0 | 5.0 | 10.0 | 5.0 | 10.0 | 10.0 | 10.0 | 10.0 | 10.0 | 10.0 | 5.0 | 10.0 |
| C max (ng mL−1) | 306 ± 53 | 1192 | 880 | 599 ± 3 | 427 | 170 ± 51 | 1533 | 1340 ± 107 | 239 ± 6 | |||
| t max (h) | 0.25 | 0.8 | 1.1 | 3.3 ± 0.7 | 0.5 | 0.25 | 1.3 ± 0.3 | 0.8 | 4.7 ± 1.3 | 2 | 3.3 ± 0.7 | 6 |
| t 1/2 (h) | 2.4 | 2.2 | 1.6 | n.d | 3.1 | 2.3 | 6.6 ± 1.6 | 3.3 | 1.2 ± 0.05 | — | — | — |
| AUC0−∞ (ng h mL−1) | 1406 | 4088 | 2482 | 1395 ± 281 | 3895 | 2993 | 4833 ± 797 | 2126 | 954 ± 209 | 16 429 | 8360 ± 540 | 2757 ± 114 |
| F (%) | 32 | 64 | 31 | 30 ± 6 | 64 | 51 | 50 ± 8 | 52 | 16 ± 3 | 102 | 42 ± 3 | 50 ± 3 |