Table 8. Preliminary ADME and Binding Data of Novel and Previously Reported A2BAR Antagonists.
| microsomal
stability |
CYP3A4 IC50 (μM)e or % inh. at 10 μMf |
||||||
|---|---|---|---|---|---|---|---|
| compound | solubility (μM)a | percentb | t1/2c | Clintd | DBF | 7-BFC | hA2BKi (nM) |
| II (ISAM-140)30 | 25.2 | 2.90 ± 0.37 | 3.49 ± 0.2 | ||||
| 14b | 62.0 | 20.97 | 28.93 | 21.65 | >10 (39%) | >10 (58%) | 11.9 ± 1.1 |
| 16b (ISAM-163) | 47.5 | 19.83 | 27.40 | 20.07 | >10 (40%) | >10 (63%) | 3.05 ± 0.7 |
| 16j (ISAM-161) | 23.7 | 22.75 | 28.14 | 18.60 | 3.68 ± 0.47 | >10 (54%) | 5.03 ± 0.3 |
| 16r (ISAM-157) | 70.7 | 32.13 | 36.79 | 14.23 | 2.26 ± 0.30 | >10 (52%) | 5.23 ± 0.4 |
| IV (ISAM-142)30 | 26.1 | 2.68 ± 0.53 | 11.4 ± 0.5 | ||||
| 15j | 58.2 | 16.83 | 21.13 | 26.44 | >10 (47%) | >10 (11%) | 44.3 ± 1.4 |
| 16l (ISAM-M89A) | 21.9 | 41.02 | 44.80 | 11.68 | 6.36 ± 1.02 | >10 (44%) | 6.10 ± 0.7 (A2B) 176 ± 4 (A2A) |
| X(31) | 39.7 | 5.92 ± 0.68 | 43.4 ± 1.3 | ||||
| 18b (ISAM-R324A) | 64.6 | 35.15 | 40.8 | 12.83 | >10 (31%) | >10 (52%) | 6.10 ± 0.3 |
| PSB-603(28) | 0.2 | 0.553 | |||||
| progesterone | 6.7 | ||||||
| prazosin | 31.3 | ||||||
| testosterone | 7.11 | 16.13 | 32.44 | ||||
| ketoconazole | 0.008 μM | 0.027 μM | |||||
a
Solubility in 1:99 DMSO/PSB buffer.
b
Percentage remanent (sampling time 60 min).
c
t1/2 in min.
d
Intrinsic clearance in microliters per minute per milligram of protein.
e
IC50 value obtained by extrapolation with analysis software.
f
Due the low activity shown at CYP3A4, the percentage of inhibition at 10 μΜ is reported.