Table 3. Profiling of 1 and 13a.
| parameter | 1 | 13 |
|---|---|---|
| MW (g/mol) | 468.91 | 458.50 |
| ALogP (LiveDesign 8.6) | 4.7 | 3.6 |
| AlogD (LiveDesign 8.6) | 5.3 | 4.0 |
| tPSA (LiveDesign 8.6) (Å2) | 118.1 | 94.8 |
| TNKS1 (IC50, nM) | 29 | 127 |
| TNKS2 (IC50, nM) | 6.3 | 14 |
| PARPs/ARTDs (IC50, μM), ARTD1/2/3/4/7/8/10/12 | >10 | >10 |
| HEK293 cells (IC50, nM) | 19 | 19 |
| kinetic solubility, PBS, pH = 7 (μM) | 12 | 95.7 |
| Caco-2 A–B: Papp (10–6 cm/s) | 10.0 | 39.5 |
| Caco-2 efflux ratio | 4.17 | 0.610 |
| microsomal stability, human/mouse, Clmt ((μL/min)/mg protein) | 242/204 | <15/37 |
| hepatocyte stability, human/mouse/dog/rat/cynomolgus, Clint ((μL/min)/106 cells) | 9.8/ND/ND/ND/ND | <0.1/28/<0.1/3.8/<0.1 |
| CYP3A4 inhibition (IC50, μM) | 1.26 | >25 |
| mouse plasma stability t1/2 (min) | 880 | |
| mouse PPB (%) | 93.92 | |
| hERG inhibition (IC50, μM) | >25 | |
| Ames test | nongenotoxic | |
| Cerep safety panel, 44 targets (10 μM) | clean (A2A, 53% inhib) | |
| bioavailability F (%) | 47 | 107 |
| po PK mouse t1/2 (h) | 1.5 | 0.67 |
| po PK mouse Cl ((L/h)/kg) | 34.0 | 2.09 |
| po PK mouse Vd (L/kg) | 74.2 | 2.03 |
| po PK mouse AUC0→t | 145 | 2384 |
a
ND = not determined.