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. 2018 Jul 13;9(8):809–814. doi: 10.1021/acsmedchemlett.8b00200

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
a

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.

b

Intrinsic clearance measured from fresh rat/dog hepatocytes and cryopreserved human hepatocytes, Clint.

c

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.

d

Solubility in aqueous phosphate buffer, pH 7.4 after 24 h at 25 °C.

e

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.

f

Inhibition of cytochrome P450, IC50 (1A2, 2C9, 2C19, 2D6, 3A4).

g

Inhibition of the hERG tail current was measured using a plate-based planar patch clamp system (IonWorks).