Preclinical pharmacology, ocular tolerability and ocular hypotensive efficacy of a novel non-peptide bradykinin mimetic small molecule

We sought to characterize the ocular pharmacology, tolerability and intraocular pressure (IOP)-lowering efficacy of FR-190997, a non-peptidic bradykinin (BK) B₂-receptor agonist. FR-190997 possessed a relatively high receptor binding affinity (K_i=27nM) and a high invitro potency (EC₅₀=18.3±4.4nM) for inositol-1-phosphate generation via human cloned B₂-receptors expressed in host cells with mimimal activity at B₁-receptors. It also mobilized intracellular Ca²⁺ in isolated human trabecular meshwork (h-TM), ciliary muscle (h-CM), and in immortalized non-pigmented ciliary epithelial (h-iNPE) cells (EC₅₀s=167-384nM; E_max=32-86% of BK-induced response). HOE-140, a selective B₂-receptor antagonist, potently blocked the latter effects of FR-190997 (e.g. IC₅₀=7.3±0.6nM in h-CM cells). FR-190997 also stimulated the release of prostaglandins (PGs) from h-TM and h-CM cells (EC₅₀s=60-84nM; E_max=29-44% relative to max. BK-induced effects). FR-190997 (0.3-300μg t.o.) did not activate cat corneal polymodal nociceptors and did not cause ocular discomfort in Dutch-Belted rabbits, but it was not well tolerated in New Zealand albino rabbits and Hartley guinea pigs. A single topical ocular (t.o.) dose of 1% FR-190997 in Dutch-Belted rabbits and mixed breed cats did not lower IOP. However, FR-190997 efficaciously lowered IOP of conscious ocular hypertensive cynomolgus monkey eyes (e.g. 34.5±7.5% decrease; 6h post-dose of 30μg t.o.; n=8). Thus, FR-190997 is an unexampled efficacious ocular hypotensive B₂-receptor non-peptide BK agonist that activates multiple signaling pathways to cause IOP reduction.