Table 2: Effect of IVT administration of various non-peptide B1- and B2-receptor antagonists on Dutch-belt rabbit IOP

Time Post-Dosing (Hours) Change in IOP (% relative to baseline) by Compound (50μg [0.16%] IVT)
(S)-WIN-64338 FR-165649 FR-173657 LF23-1591
(B2-selective) (B2-selective) (B2-selective) (B1-selective)
4 -4.1 ± 1.7% -0.2 ± 1.8% -22.9 ± 4.5% 2.9 ± 5.1%
5 -7.4 ± 2.3% 0.6 ± 1.4% nd 5.4 ± 4.2%
6 -7.7 ± 3.8% -1.0 ± 2.0% -7.6 ± 3.2% 9.6 ± 4.0%
8 -15.9 ± 4.9%* -4.2 ± 1.2% -15.9 ± 4.9% 5.4 ± 2.8%
24 -35.3 ± 4.0%** -6.5 ± 2.5% -13.2 ± 4.2% 1.3 ± 3.0%
30 -45.6 ± 2.9%** -9.4 ± 4.0% -12.7 ± 2.8% 4.3 ± 3.3%
48 -43.2 ± 4.0%** -10.8 ± 3.4% -9.2 ± 2.9% -13.8 ± 5.6%
72 -47.4 ± 2.9%** nd nd nd
168 -16.2 ± 2.3%* nd nd nd
Receptor Antagonist Potencies
(IC50s)
298 ± 81 nM
(n=3)
195 ± 80 nM
(n=6)
323 ± 150 nM
(n=6)
nd

Data are mean ± SEM from 7-10 rabbits per group. The mean baseline IOP of these animals ranged from 27.5 ± 0.4 to 28.4 ± 0.4mmHg during the course of these studies. The vehicle had minimal effect on IOP as shown in Figure 2. No effects on IOP of (S)-WIN-64338 ivt were observed in the contralateral eyes. The receptor antagonist potencies refer to the non-equilibrium blocking effects of the antagonists of BK-induced [Ca2+]i mobilization in isolated primary h-TM, h-CM and ih-NPE cells to illustrate the differences in relative affinities of the compounds for their respective BK-receptor sub-type(s), primarily the B2-receptor. *p<0.01; **p<0.001 relative to vehicle baseline IOP or relative to IOP at 4 h post-dose. nd denotes not determined. IOP-lowering data for 10μMg (0.033%) ivt injection of (S)-WIN-64338 are shown in the Results section.