Table 1.
In vitro Inhibition of Recombinant ATX/ENPP2.
Table 2.
In vitro Inhibition of Plasma LysoPLD Activity.
Figure 1.
In vitro Inhibition of LPA Formation by ONO-8430506 in Human and Rat Plasma.
Human plasma (A) and rat plasma (B) were incubated at 37°C for 1 h. Plasma samples before and after incubation were immediately cooled on ice, LPA was extracted and five molecular species of LPA were quantified by LC-MS/MS. The diagrams on the left show the results from incubation of plasma alone, while the diagrams on the right show the inhibition of LPA formation when plasma was incubated with various concentrations of ONO-8430506. Results are means ± S.D. of four separate experiments in human plasma and two or three experiments in rat plasma.
Figure 2.
Pharmacokinetics and Pharmacodynamics of the Inhibitor in Rats.
Blood was collected at various time points after single oral administration of 3 or 30/kg ONO-8430506 to rats. The time course of changes in plasma concentration of ONO-8430506 (A), plasma ex vivo LysoPLD activity (B), and plasma concentrations of various LPAs (C) are shown. Plasma LysoPLD activity is shown relative to LysoPLD activity before administration of the compound. Quantify limit of each LPA from plasma was 5 ng/ml. Results are mean ± S.D. for three rats in each group.
Figure 3.
LPA Stimulate the Contraction of Isolated Rat Urethra.
The increases in contractile force of isolated rat urethra treated with 18:3-LPA or phenylephrine added to the Magnus apparatus are shown relative to the results for phenylephrine at 100 µM (100%). Results are mean ± S.D. for four urethral specimens.
Figure 4.
ONO-8430506 regulates in vivo Rat Urethral Tension.
Male SD rats were anesthetized with urethane and the vehicle, tamsulosin (α1-blocker), or ONO-8430506 were administered intraduodenally. The histograms show the maximum percent decreases (%) in IUP (A and B) and maximum percent decreases in mean blood pressure (C and D) during 20-min after intraduodenal administration of each drug. Results are means ± S.E. for nine or ten rats per group. Comparisons between the treatment groups and vehicle control group were performed using the Dunnett's tests or Student's t tests. ## p<0.01; ### p<0.001 by Student's t test vs Vehicle. ** p<0.01, *** p<0.001 Dunnett test vs Vehicle. $<0.05 by Student's t test vs Tam 0.3. A correlation between the relative inhibition (vs. vehicle control) of plasma LysoPLD activity (%) by the compound and the decreases in IUP (%) at 20 min after intraduodenal administration are shown (E).