Table 3. Physicochemical, Pharmacokinetics, and Other Properties of Compounds 12 and 21.
properties | Cpd 12 | Cpd 21 |
---|---|---|
hu/rat/dog/mo ppb; fu (%)a | 13; 6; 44; 46 | 4; 2; 30; 21 |
rat/dog/hu hepatocyte Clint (μL/min/106 cell)b | 3.4; 5.1; 2.8 | 5.7; 8.8; 4.1 |
rat/dog pharmacokinetic parameters | ||
clearance: Cl (mL/min/kg)c | 25; 49 | 7.8; 48 |
Vd (L/kg)c | 5.5; 20 | 2.8; 14 |
bioavailability: F (%)c | 26; 43 | 41; 35 |
terminal half-life (h) | 4.1; 6.2 | 5.6; 4.7 |
aqueous solubility (μM)d | 870 | 880 |
intrinsic permeability (10–6 cm.s–1)e | 2.8 | 2.0 |
CYP inhibition IC50 (μM)f | >30 (all) | >30 (all) |
hERG IC50 (μM)g | 24 | 15 |
Plasma protein binding (ppb) in human, rat, dog, and mouse plasma, fraction unbound fu; determined from DMSO stock solution by equilibrium dialysis in 10% plasma.
Intrinsic clearance measured from fresh rat/dog hepatocytes and cryopreserved human hepatocytes, Clint.
From plasma concentrations in male Han Wistar rats and male Beagle dogs (at least n = 2), compound administered at 1 mg/kg i.v. and 2 mg/kg p.o. as a formulation in 0.5% (w/v) HPMC and 0.1% (w/v) Tween 80 in water for the oral arm and as a solution formulation in 5% DMSO and 95% SBE-β-cyclodextrin (30% w/v in water) for the iv arm. Intravenous parameters (including half-life) calculated from an intravenous bolus; bioavailability, from oral and i.v. AUC.
Solubility in aqueous phosphate buffer, pH 7.4 after 24 h at 25 °C.
Intrinsic permeability measured in Caco-2 cell line, A pH 6.5, B pH 7.4, measured in the apical-to-basolateral (A to B) direction in the presence of an efflux inhibitor.
Inhibition of cytochrome P450, IC50 (1A2, 2C9, 2C19, 2D6, 3A4).
Inhibition of the hERG tail current was measured using a plate-based planar patch clamp system (IonWorks).