Figure 1.
Chemical structure of FTY720 (A) and BAF312 (B), the latter as reported by Thompson Integrity and as referred to as BAF312 throughout the publication.
Table 1.
S1P receptor subtype selectivity of FTY720-P and BAF312, EC50 values reported in nM.
Figure 2.
Effect of FTY720 on mean arterial pressure (MAP, Panel A) and heart rate (HR, Panel B) in anesthetized rats.
Plasma concentrations at the end of each infusion period and at the end of the post-treatment period are shown in (A) in µM. At the end of each infusion period mean arterial pressure decreased to −9±3, −22±4, and −24±4 mmHg below baseline and heart rate decreased to −71±26, −139±37, and −173±26 beats/min below baseline values; *p<0.05 vs. the vehicle control group.
Figure 3.
Effect of BAF312 on mean arterial pressure (MAP, Panel A) and heart rate (HR, Panel B) in anesthetized rats.
Plasma concentrations at the end of each infusion period and at the end of the post-treatment period are shown in (A) in µM. BAF312 elicited an acute decrease in heart rate; 10-min into the first infusion period heart rate decreased to −51±8 beats/min (vehicle = −6±4 beats/min). However, despite an increase in plasma concentrations of BAF312 throughout the infusion period HR returned toward baseline and was not different from vehicle controls during the latter half of the 60-min infusion; *p<0.05 vs. the vehicle control group.
Figure 4.
Effect of FTY720 (0.3, 1.0, 3.0, 10.0 mg/kg p.o.) on mean arterial pressure (A) and heart rate (B), and effect of BAF312 (0.3, 3.0, and 30 mg/kg p.o.) on mean arterial pressure (C) and heart rate (D), in conscious, telemetry-instrumented, rats after a single oral dose.
Values are shown as 24-hr mean MAP (mmHg) and heart rate (beats/min, BPM) change from baseline. FTY720 elicited dose-dependent and sustained increases in MAP after a single oral dose, an effect that reached statistical significance in the 3 and 10 mg/kg dose groups (to 13.5±1.8 and 19.9±2.8 mmHg above baseline, respectively). Heart rate was acutely reduced (vs. vehicle) only in the 10 mg/kg group on day 1 (−13±6 beats/min). Thereafter, changes in heart rate were not different from vehicle control rats. BAF312 had no effect on MAP or HR at any dose tested in the study. Statistical analysis was performed on 24-hr mean values (*p<0.05 one-way ANOVA vs. vehicle with Dunnett’s post-test).
Table 2.
Plasma concentrations of FTY720 and the phosphorylated form of FTY720, (S)-FTY720-P, after a single oral dose (0.3, 1.0, 3.0, 10.0 mg/kg) at 4, 8, 24, 48, and 72 hrs post-dose; values quantified by MS and are shown in nM (mean±SEM).
Table 3.
Plasma (nM) concentrations of FTY720 and the phosphorylated form of FTY720 after oral administration (0.5, 1.5, 5.0 mg/kg/d) or BAF312 after oral administration (0.3, 3.0, 30.0 mg/kg/d) at 4, 8, and 24 hrs post-dose on Day 1 and at 0, 4, 8, and 24 hrs post-dose on the last day of the study; values were quantified by mass spectrometry and are shown as mean±SEM.
Figure 5.
Effect of FTY720 and BAF312 on mean arterial pressure (MAP) and heart rate (HR) in conscious, telemetry-instrumented, rats during 10 days of daily oral administration.
At doses that elicited no significant bradycardia, FTY720 elicited dose-dependent hypertension whereas BAF312 had no affect on MAP values at any dose tested during the study. FTY720 elicited dose-dependent increases in MAP at all doses tested (0.5, 1.5, and 5.0 mg/kg/d); 24-hr mean values over the treatment period increased 8.4±0.4, 12.8±0.4, and 16.2±0.8 mmHg, respectively, (vehicle = 3.7±0.5 mmHg) and values reached statistical significance in all treated groups (*p<0.05 vs. vehicle). However, BAF312 elicited no significant increase in mean arterial pressure during the study; average changes in 24-mean values during 14-days of treatment in the 0.3, 3.0, and 30 mg/kg/d dose groups were 3.0±0.5, 1.1±0.5, and 0.1±0.5 mmHg, respectively.