TABLE 6.
Pharmacological properties of ring-linker compoundsa
| Molecule | Microsome stability (t1/2 [min]) |
Mouse oral PK (mean ± SD)b |
|||
|---|---|---|---|---|---|
| Mice | Humans | Cmax (μM) | AUC (min ⋅ μmol/liter) | Concn (μM) in pooled mouse feces | |
| 2114 | 7.7 | 15.2 | 7.5 ± 2.4 (3) | 1,854 ± 103 (3) | 11.4 ± 4.1 (3) |
| 2067 | 3.1 | 9.3 | 65.2 ± 13.3 (3) | 17,263 ± 5,167 (3) | |
| 2091 | 2 | 9.4 | |||
| 2093 | 3.2 | 8.3 | 5.8 ± 1.54 (3) | 1,863 ± 658 (3) | 31.1 ± 3.5 (3) |
| 2069 | 3.6 | 8.2 | 21.8 ± 8.8 (3) | 3,932 ± 431 (3) | |
| 2139 | 11.7 | 20.1 | 40.7 ± 10.6 (3) | 10,404 ± 2,589 (3) | 36.2 ± 3.7 (3) |
| 2259 | 29.4 | 32.7 | 25.8 ± 16.2 (3) | ||
| 2138 | 5.8 | 15 | 30.8 ± 1.3 (3) | 6,269 ± 1,806 (3) | 43.6 ± 3.8 (3) |
| 2258 | 13.8 | 25.5 | |||
| 2207 | 5.3 | 25.1 | 30.8 ± 6.5 (3) | 3,048 ± 863 (3) | |
| 2240 | 24.2 | 42.3 | 11.1 ± 11.8 (3) | 856 ± 813 (3) | 846 ± 220 (3) |
| 2080 | 1.6 | 8 | 25.4 ± 8.6 (3) | 5,092 ± 1,466 (3) | 17.9 ± 5.4 (3) |
| 2242 | 4.5 | 7.7 | 2.5 ± 0.7 (3) | 512 ± 51 (3) | 52.7 ± 16.2 (3) |
a
In vitro metabolic stability (t1/2) was measured in mouse and human liver microsomes. Pharmacokinetic studies in mice (n = 3 per compound) were performed with a single peroral dose at 50 mg/kg in MMV vehicle (defined in Materials and Methods). The microsome half-lives for compounds 2093 and 2114 were previously published (27).
b
n values are indicated in parentheses.