Table 6.
Physicochemical, in vitro ADMEa, and oral bioavailability profile of selected analogues
| Compd | Aqueous Solubility (μM)a |
Plasma Stability t1/2(h) | Plasma Protein Binding (%)b |
Microsomal Stability CLintc (Phase I / Phase II) | Caco-2 Pappd (10−6 cm/s) | Fg (%) | ||||
|---|---|---|---|---|---|---|---|---|---|---|
| Human | Mouse | Human | Mouse | Human | Mouse | Ae to Bf | B to A | |||
| 11 | 19 | >24 | >24 | 86 | 50 | 5.0/2.0 | 18/4.4 | − | 34 | |
| 19g | 11 | >24 | >24 | 86 | 80 | 3.4/< 0.1 | 25/5.2 | 24.8 | 27.6 | − |
| 19h | 31 | >24 | >24 | 91 | 82 | 14/<0.1 | 92/5.2 | 18.6 | 26.9 | 11 |
| 19k | 31 | >24 | >24 | 94 | 90 | 7.6/< 0.1 | 28/1.6 | − | − | 46 |
| 191 | 6.7 | >24 | >24 | 80 | 69 | 2.4/0.1 | 4.2/2.0 | − | − | − |
| 19o | 9.5 | >24 | >24 | 89 | 82 | 5.8/3.2 | 22/10 | − | − | 25 |
a
Aqueous stability of selected analogues were determined in Dulbecco’s Phosphate-Buffered Saline (DPBS). All analogues showed excellent stability with remaining percentage at 24 h > 90%.
b
Percent of fraction bound.
c
CLint: intrinsic clearance, μl/min/mg protein.
d
Papp: The apparent permeability coefficient.
e
A: apical side.
f
B: basolateral side.
g
F: Oral bioavailability in mice.