Table 5.
The effect of introduction of a nitrogen atom into the indole core of HIV-1 AIs on antiviral activity, physicochemical properties and select developability attributes [35]
 | |||||
|---|---|---|---|---|---|
| Compound # | 146 | 147 | 148 | 149 | 150 |
| Property | indole | 4-N | 5-N | 6-N | 7-N |
| EC50 (nM) | 4.0 | 1.6 | 576 | 21.6 | 1.7 |
| CC50 (μM) | 200 | >300 | >300 | >300 | 280 |
| LogD6.5 | 1.9 | 0.9 | 1.2 | 1.5 | 1.8 |
| cLogP/cLogD7.0 | 2.70/2.70 | 1.92/1.92 | 1.36/1.32 | 2.36/2.30 | 1.79/1.79 |
| PSA (Å)2 | 73.5 | 86.4 | 86.4 | 86.4 | 86.4 |
| Cryst. sol. at 25 °C, pH 6.5 (mg/mL) | 0.016 | 0.93 | 0.42 | 0.49 | 0.94 |
| mp (oC) | 212–216 | 298–301 | 227 | 249–253 | 146–148 |
| pKa | 10.9 | 5.0/9.8 | 6.2/9.8 | 6.0/9.3 | 2.0/9.7 |
| Caco-2 Pc (nm/sec) | 169 | 76 | 19 | <15 | 168 |
| HLM t½ (min) | 16.9 | >100 | >100 | 38.5 | 49.5 |
| CYP 450 3A4 inhibition IC50 (μM) | >40/>40 | >40/>40 | 18/9.3 | >40/>40 | >40/>40 |
| hERG inhibition IC50 (μM) | >80 | >80 | >80 | >80 | >80 |
cLogP/cLogD7.0 and PSA values are calculated using Advanced Chemistry Development (ACD/Labs) Software V11.02 (©1994-2021 ACD/Labs) with the data abstracted from SciFinder®
CYP 3A4 inhibition was assessed using the 2 substrates benzyloxy-4-(trifluoromethyl)coumarin and 7-benzyloxyresorufin.