Table 1. In Vitro PDE Selectivity Profile, in Vitro ADME, and Physicochemical Properties of 6.
| PDE
selectivity profile |
ADME
and physicochemical properties |
||
|---|---|---|---|
| subtype | IC50 (nM) | ||
| hPDE1A | >10000 | hLMa | 7 |
| hPDE2A | 29 | rLMa | 13 |
| hPDE3B | >10000 | kinetic solubility at pH 7.4 (μM)b |
>1000 |
| hPDE4D | 5890 | pKac | 2.7 |
| hPDE5A | >10000 | formulatability (mg/mL)d | 4 |
| hPDE6AB | >10000 | CYP450 (>50% inhibition @ 5 μM)e |
none |
| hPDE7A | >10000 | AMESIIf | negative |
| hPDE9A | >10000 | ||
| rPDE10A | 480 | ||
| hPDE11A | 6920 | ||
a
Percent metabolized after incubating 1 μM solution 15 min with rLM or hLM at 37 °C.
b
Compound concentration after 4 h incubation in buffer pH 7.4.
c
Determined by potentiometric titration (25 °C).
d
20% HPβCD at pH > 3.5.
e
Enzymatic inhibition of CYP1A2, 2C9, 2D6, 2C19, and 3A4.
f
Adaptation of the colorimetric AMESII Mutagenicity Assay kit from Xenometric. Compound concentration 125 μg/mL.