Table 1.
Optimization of P3
|
EC50 (μM) |
β5 IC50 (μM) | Permeability | Metabolic stabilityc m/hLM Clint | Kinet. Solu. | Cytotox. | cLogP | |||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| ID | P5 | P3 | 3D7 | Pf20S | c-20S | i-20S | PAMPA | Ratio /MDR1 | ||||
| 1* | A |
|
0.003 | 0.014 | 4.0 | >100 | 151 | >0.77/<4 | 270/11.2 | <1.4 | 93 | 4.7 |
| 2 | A | H | >2.8 | >100 | 3.7 | 2.7 | <18 | 4.1/0 | −4/−17.4 | 4.1 | 104 | 2.2 |
| 3 | A |
|
>2.8 | 14.6 | >100 | >100 | 44 | >8.7/<1 | −11.7/−12.7 | 14 | 98 | 2.4 |
| 4 | A |
|
>2.8 | >100 | >100 | >100 | 73 | 14/0 | −11.7/−2 | <1.2 | 98 | 3.1 |
| 5 | A |
|
0.59 | 0.9 | >100 | >100 | 81 | >2.5/<2 | 37.7/37.7 | <1.9 | 91 | 3.8 |
| 6 | A |
|
0.62 | 3.8 | >100 | >100 | 95 | >39/<1 | 25.2/−4 | <1.4 | 94 | 4.2 |
| 7** | B |
|
0.0002 | 0.003 | 0.38 | 33.9 | 214 | 31/5 | >768/644 | 3.8 | 77 | 5.3 |
| 8 | B |
|
1.7 | 5.9 | 2.9 | 7.2 | 237 | 47/2 | >768/522 | 22 | 105 | 4.8 |
| 9 | B |
|
0.010 | 0.095 | 1.5 | 9.6 | 30 | 26/1 | 73.9/15.5 | >140 | 97 | 4.0 |
| 10 | B |
|
0.001 | 0.014 | 0.14 | 1.4 | 264 | 46/3 | >768/687 | >140 | 110 | 3.4 |
| 11 | B |
|
0.003 | 0.013 | 17 | 54 | 171 | 100/1 | >768/238 | >130 | - | 3.7 |
*
: compound reported in REF 22
**
: compound reported in REF 22; PAMPA unit: nm/sec at pH 7.4; MDR unit: ratio (B→A/A→B); A→B, nm/sec; Metabolic stability m/hLM Clint: mouse/human liver microsomes and unit- μL/min/mg; Kinet. Solu.: Kinetic solubility at pH 6.8 (μg/mL); Cytotox.: cytotoxicity, % viability of HepG2 cells at 30 μM. “-”: not tested.