Table 2. Comparison of Hexahydro-5H-cyclopenta[f]quinolines 8 and Hexahydro-1H-cyclopenta[a]naphthalenes 3a.
| cmpd | X | R | RORγt GAL4 EC50 (nM) | IL-17 hWB EC50 (nM) | LM h, m (% rem)b | Caco-2 Pc, nm/s (efflux)c | PB % free (h, m)d | rCYP 2C8, 2C9, 2C19, 3A4 IC50 (μM)e |
|---|---|---|---|---|---|---|---|---|
| 8a | N | A | 3.9 | 67 ± 13 | 100, 100 | 180 (0.5) | nd, 2.3 | 8.3, 11, >20, >20 |
| 8b | N | B | 6.0 ± 2.7 | 101 ± 45 | 100, 87 | 120 (0.5) | nd, 1.8 | 6.3, 8.5, 17, 9.1 |
| 8c | N | C | 8.4 ± 3.8 | 67 ± 15 | 100, 82 | 81 (2.2) | nd, 2.2 | 16, 9.4, 16, >20 |
| 8d | N | D | 12 ± 4.8 | 260 ± 120 | 97, 100 | nd | nd | nd |
| 8e | N | E | 2.5 ± 1.7 | 26 ± 13 | 89, 98 | 110 (1.2) | 2.2, 1.5 | 7.6, >20, >20, >20 |
| 3a | CH | A | 3.7 ± 2.3 | 50 ± 14 | 100, 92 | 106 (0.5) | 0.5, 0.6 | 12, 12, 19, 11 |
| 3b | CH | B | 2.5 ± 2.1 | 54 ± 20 | 97, 86 | 150 (0.5) | 0.2, 0.3 | 6.5, nd, 7.7, 5.8 |
| 3c | CH | C | 8.7 | 50 ± 25 | 100, 95 | 73 (1.4) | nd, 0.2 | 13, 5.5, >20, >20 |
| 3d | CH | D | 5.5 | 130 ± 32 | 89, 83 | 76 (0.9) | nd, 0.4 | 5.0, 9.2, 15, 0.25 |
| 3e | CH | E | 2.5 ± 0.80 | 39 ± 23 | 98, 84 | 64 (0.5) | nd, 0.4 | 3.2, 12, 15, >20 |
a
See the Supporting Information for assay protocols. Values are the means of two or more experiments. SDs are provided for means of three or more experiments. nd = not determined.
b
Percent remaining after 10 min of incubation with human or mouse LM.
c
Pc in nm/s in the apical to basal direction in Caco-2 cells. Values in parentheses are the efflux ratios (BA/AB).
d
Protein binding, % free in human or mouse serum.
e
Inhibition of recombinant cytochrome P450 isoforms. Isoforms not shown are >20 μM.