Figure legends:
Figure 1: Chemical structure of Org 48775-0; 4,6-bis(4-fluorophenyl)-5-(4-pyridinyl)-2H-pyrazolo[3,4-b]pyridine-2-propanol.
Figure 2: Schematic overview of the study design
All study parts included male volunteers only, except for the female cohort; PL=placebo.
Figure 3: Pharmacokinetic profile of Org 48775-0
Pharmacokinetic profile of Org 48775-0 per dose average (on y-axis) over time (on x-axis), with SD as error bars. Panel A : SAD; 0.3 mg, 1 mg and 3 mg Org 48775-0 are not shown; triangle closed: 10 mg; triangle open: 30 mg; diamond closed: 60 mg; diamond open: 100 mg; triangle down closed: 200 mg; triangle down open: 400 mg; plus: 600 mg;Panel B : MAD; circle closed: 30 mg (n=8); circle open: 70 mg (n=8); plus: 150 mg (n=8). Panel C : Food effect; circle closed: 100 mg in fasted condition (n=6); circle open: 100 mg in fed condition (n=6). Panel D : Gender differences up to 24 hours; circle closed: 100 mg in females (n=6); circle open: 100 mg in males (n=11).
Figure 4: Ex vivo inhibition of LPS-induced TNFα release by Org 48775-0
Ex vivo inhibition of LPS-induced TNFα release average per Org 48775-0 dose (on y-axis) over time (on x-axis) with SD as error bars.Panel A : SAD; circle closed: placebo; circle open: 0.3 mg; square closed: 1 mg; square open: 3 mg; triangle closed: 10 mg; triangle open: 30 mg; diamond closed: 60 mg; diamond open: 100 mg; triangle down closed: 200 mg; triangle down open: 400 mg; plus: 600 mg. Panel B : MAD; circle closed: placebo (n=6); circle open: 30 mg (n=8); square closed: 70 mg (n=8); square open: 150 mg (n=8). Panel C : Food effect; circle closed: 100 mg in fasted condition (n=6); circle open: 100 mg in fed condition (n=6). Panel D : Gender differences; circle closed: 100 mg in females (n=6); circle open: 100 mg in males (n=11).
Figure 5: In vitro versus ex vivo Org 48775-0 effect
LPS-induced TNF alpha release for a representative subject. Ex vivo Org 48775-0 effect (y-axis) versus in vitro Org 48775-0 effect (x-axis), linked based on Org 48775-0 concentration (at 0, 1, 4, 7, 10, 24, 48 and 72 hours; black circles). The dotted line indicates the perfect relationship (ex vivo effect = in vitroeffect).