Table 5.
Summary of physicochemical and molecular properties, Notum inhibition and ADME data for 24.
| 24 | |
|---|---|
| Physicochemical and molecular properties | |
| mol wt | 374 |
| cLogP | 2.1 |
| LogD7.4 | 1.6 |
| TPSA (Å2) | 74.6 |
| CNS MPO | 5.9 |
| Notum inhibitiona | |
| OPTS, IC50 (nM) | 3.9 ± 0.8 (n = 4) |
| TCF-LEF, EC50 (nM) | 220 ± 64 (n = 3) |
| ADME profileb | |
| Aq. solubility (μg/mL)/(μM) | 45/120 |
| Mouse plasma protein binding (PPB) (%) | 78.1 |
| Mouse brain binding (%) | 84.4 |
| MLM, Cli (μL/min/mg protein) | 6.9 |
| Mouse plasma stability, % remaining at 120 min (%) | 110 |
| CYP1A2 inhibition, IC50 (μM) | >30 |
| CYP2B6 inhibition, IC50 (μM) | >30 |
| CYP2C9 inhibition, IC50 (μM) | >30 |
| CYP2D6 inhibition, IC50 (μM) | >30 |
| CYP3A4 inhibition, IC50 (μM) | >30 |
| MDCK-MDR1, AB/BA Papp (×10−6 cms−1) | 23/56 |
| MDCK-MDR1, efflux ratio (ER) | 2.4 |
a
See footnotes Table 4.
b
In vitro ADME studies reported in this work were performed by GVK Biosciences (Hyderabad, India).